Scientific Program

Day 1

KEYNOTE SPEAKERS
  • BCL-XL directly modulates RAS signalling to favour cancer cell stemness

    Center for Research in Cancerology and Immunology Nantes-Angers (CRCINA)
    France
    Biography

    Dr Philippe Juin obtained his PhD degree in 1995 for his work on mitochondrial assembly. During his post-doc in the UK, he defined the mitochondrial apoptotic pathway as one major intrinsic tumor suppressor mechanism triggered by oncogene deregulation. As an Associate Researcher at INSERM, he led increasingly ambitious investigations of the regulation of the mitochondrial apoptotic pathway by Bcl-2 family members in human cancer cells and he created in 2012 an INSERM team that specifically focusses on the role of this pathway in stress adaptation and tumor escape. This team gained international recognition for its fundamental and translational research on the regulation of therapeutic response and tumor progression by BCL-2 family members (Nature Rev. Cancer 2013, Cell Rep. 2016, EMBO Rep. 2018 in press). This team contributed to establish that changes in mitochondrial apoptotic priming are at the core of breast cancer cells response to cytotoxic stress and treatments, being influenced by oncogene signaling, tumor suppressor pathways, therapy and tumor context. This team recently established a new function of BCL-2 members, that contributes contributing to the self renewal of breast cancer initiating cells, and defined the molecular events involved (Nature Comm., 2017).

    Abstract

    In tumours, accumulation of chemoresistant cells that express high levels of anti-apoptotic proteins such as BCL-XL is thought to result from the counter selection of sensitive, low expresser clones during progression and/or initial treatment. We herein show that BCL-XL expression is selectively advantageous to cancer cell populations even in the absence of pro-apoptotic pressure. In transformed human mammary epithelial cells BCL-XL favours full activation of signalling downstream of constitutively active RAS with which it interacts in a BH4 dependent manner. Comparative proteomic analysis and functional assays indicate that this is critical for RAS-induced expression of stemness regulators and maintenance of a cancer initiating cell (CIC) phenotype. Resistant cancer cells thus arise from a positive selection driven by BCL-XL modulation of RAS-induced self-renewal, and during which apoptotic resistance is not necessarily the directly selected trait.

  • Cancer Stem Cells: Engine of Therapy Resistance & Seeds of Tumor Recurrence

    Roswell Park Cancer Institute
    USA
    Biography

    Dean Tang, PhD, was trained as a Pathologist and is currently Professor & Chair in Department of Pharmacology & Therapeutics at Roswell Park Cancer Institute. His Master of Science thesis research (1986-1989), conducted in Dr. Hong-shen Tian’s laboratory in Wuhan University School of Medicine, focused on establishing lung cancer metastasis models. To continue his research on metastasis, Dr. Tang joined Dr. Ken Honn’s lab at Wayne State University (WSU) in 1989 to study the role of integrin receptors in mediating tumor cell – extracellular matrix interactions, tumor cell invasion, and tumor cell extravasation. Dr. Tang obtained his PhD in Cancer Biology in 1994 and stayed at WSU for a few years to explore apoptosis-based anti-prostate cancer therapeutics. In 1998, he was awarded a Burroughs-Wellcome Hitchings-Elion post-doctoral Fellowship to study oligodendrocyte precursor cell (OPC) development in Dr. Martin Raff’s lab in Medical Research Council (MRC) Laboratory for Molecular & Cellular Biology (LMCB) of University College London (UCL, UK). Dr. Tang returned to America in June of 2000 to join the MD Anderson Cancer Center Department of Epigenetics and Molecular Carcinogenesis till May of 2016.

    Abstract

    Our lab has been studying basic principles governing generation of tumor cell heterogeneity via cancer stem cells (CSCs). By employing prostate cancer (PCa) as a model, we have demonstrated that PCa cells are not all equal with respect to their tumorigenic and metastatic potential. Rather, there exist stem cell-like PCa cells that are mostly undifferentiated (i.e., PSA-/lo), relatively quiescent, and resistant to clinical therapies including castration. These prostate CSCs (PCSCs) preferentially express stem cell genes and epigenetic landmarks, can undergo asymmetric cell division and regenerate differentiated (PSA+) cells, and become greatly enriched in treatment-failed tumors (Cell Stem Cell, 2012; Oncotarget, 2015, 2016; Clin Cancer Res, 2016). Several tumor-suppressive miRNAs, including miR-34a, miR-141, and miR-128, potently suppress the PCSC properties and PCa metastasis (Nat Med, 2011; Cancer Res, 2014; Nat Commun, 2017). Both PSA- normal human prostate basal/stem cells (Nat Commun, 2016) and PSA-/lo PCSCs express an intrinsic neurogenesis program that causally regulates their stem/progenitor cell activities. Of clinical relevance, PCa cell heterogeneity, in particular, AR heterogeneity, has a great impact on PCa response to current clinical therapeutics (Nat Commun, In revision). While we are uncovering novel therapeutics using organoids-based high throughput screening that can specifically target undifferentiated CSCs, we are already translating some of our laboratory findings to clinical trials.

  • Inflammatory cytokines, induced by ionizing radiation, reprogram non-tumorigenic cancer cells into cancer stem cells in breast cancer.

    French National Institute of Health and Medical Research
    France
    Biography

    Dr Lagadec is an assistant professor at the French National Institute of Health and Medical Research. He received his PhD in 2007 on TrkA signaling in breast cancer and spent 5 years as a postdoc fellowship in Dr. Pajonk’s lab, a pioneer in CSC research field. Within his time at UCLA in the Radiation Oncology Department at David Geffen School of Medicine, he got trained on CSC and was the first to demonstrated the phenotype plasticity of CSC induced by radiation treatment. Since 2012, Dr. lagadec set up is own team in the INSERM U908 laboratory in Lille, France, where he studies the molecular mechanisms involved in the reprogramming process. He develops molecular tools and an animal model to track and characterise CSC and iCSC. His domain of interest enlarges recently to understand the potential role of reprogramming in tumor dormancy and metastasis development.

    Abstract

    Identification of cancer stem cells (CSC) in solid tumours – with self-renewal, multipotency, tumorigenesis, and therapy resistance capacities – has opened path to new targeting therapeutic approaches. However, CSC targeting alone might not be sufficient to eradicate a tumour. Indeed, recent studies showed that cancer cells are plastic, and conventional therapies, such as radiotherapy, can lead to cancer cells (non-CSC) reprogramming into iCSC (induced-CSC). The goal of our work is to identify the molecular mechanisms responsible for treatment-induced CSC emergence. First, we have shown that conditioned media from irradiated non-CSC is sufficient to induce iCSC reprogramming. These results suggest that cell plasticity might be actively regulated by diffusible factors secreted by irradiated cells. By using proteins arrays and ELISA, we demonstrated that the secretion of a specific cocktail of chemokines is induced by ionizing radiation, such as CXCL1 and CCL5. Interestingly, recombinant CXCL1 and CCL5 treatments increase the sphere forming capacity (SFC) of isolated non-CSC treated population. Concomitantly, treatment with neutralizing antibodies targeting CXCL1 and CCL5 leads to a decreased CSC number (ALDH+ cells). Most importantly, treatment with neutralising antibodies through radiation treatment of xenograft in SCID mice double the survival time of the mice. Preclinical study show predictive value of CXCL1 and CCL5 expression. We also studied the expression of the corresponding chemokines receptors, by flow cytometry. First, we saw that reprogrammable ALDH- cells are enriched for CXCL1 and CCL5 receptors expressing cells compare to unsorted population or ALDH+ population (CSC). We analysed the reprogramming potential of isolated ALDH-/receptor-positive cells versus ALDH-/receptor-negative cells. The ALDH-/receptor-positive-derived cell population is more able to form spheres and overcomes the receptor-negative-derived population when the two populations are mixed and tested for their sphere forming capacity. The use of pharmacological inhibitors against the receptors induce a slight decrease of CSC. Taken together, our results indicate the involvement of chemokines, in particular CXCL1 and CCL5, in the reprogramming mechanism.

Cancer Stem Cells | Breast Cancer Stem Cells | Prostate Cancer Stem Cells | Ovarian Cancer Stem Cells | Pancreatic Cancer Stem Cells | Lung Cancer Stem Cells | Cancer Stem Cells and Metastasis
Chair
Co-Chair
Speaker
  • Angiogenin and plexin-B2 inhibition sensitizes prostate cancer stem cells to chemotherapy
    Speaker
    Guo-fu Hu
    Tufts University
    USA
    Biography

    Guo-fu Hu, PhD, is currently a Professor of Medicine, Tufts University School of Medicine, and an Investigator at Tufts Medical Center. He received his PhD from Shanghai Institute of Biochemistry, Chinese Academy of Sciences, and did his postdoctoral training in Beret L. Vallee lab located at the Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School. He established his research program first in the Department of Radiology, Brigham and Women’s Hospital, and then in the Department of Pathology, Harvard Medical School, where he raised to the rank of Associate Professor of Pathology. He moved to Tufts Medical Center in 2010.

    Abstract

    Angiogenin (ANG) and its receptor Plexin-B2 (PLXNB2) has recently been shown to dichotomously regulate the stemness of hematopoietic stem and progenitor cells (HSPC). While ANG and PLXNB2 preserve quiescence of the primitive stem cells, they promote proliferation of more differentiated progenitor cells. Here we show that ANG-PLXNB2 also dichotomously regulates the properties of cancer stem cells (CSC) and differentiated bulk cancer cells. Prostate CSCs were cloned from PC3, LNCaP, and DU145 cells, and shown to have self-renewal, differentiation, and tumor-initiating capacities. While ANG-PLXNB2 enhance proliferation of differentiated prostate cancer cells, they restrict proliferation of CSCs and promote quiescence through specific cleavage of 5S rRNA. Monoclonal antibodies against both ANG and PLXNB2 were found to mobilize CSC out of quiescence, sensitive them to chemotherapy, and prevent disease relapse.

  • Phage display library screening identifies novel binding peptides that preferentially target castration-resistant PSA-/lo prostate cancer stem cells
    Speaker
    Kiera Rycaj
    Roswell Park Cancer Institute
    USA
    Biography

    Kiera Rycaj, Ph.D, is currently Assistant Professor at the Roswell Park Comprehensive Cancer Center (RPCCC) in Buffalo, NY, USA. Dr. Rycaj obtained her Ph.D from the University of Texas M.D Anderson Cancer Center (MDACC) in 2012 Her Ph.D thesis work focused on the expression and biological functions of HERV-K (Human Endogenous Retrovirus – K) in breast and ovarian cancer (OC) cells. Her work has demonstrated that the HERV-K env protein not only is expressed on the surface of breast cancer and OC cells but also can function as TAA (tumor-associated antigen) to elicit T-cell and antibody responses. She developed HERV-K specific vaccines and demonstrated their utility in killing autologous patient cancer cells. She conducted her postdoc training in Dr. Tang’s laboratory during 2012-2015 and her work focused on elucidating prostate cancer (PCa) cell heterogeneity and therapeutically targeting the phenotypically undifferentiated AR-/lo(PSA-/lo) prostate cancer stem cells (PCSCs). Her recent published study on high-throughput screening shows that treatment-reprogrammed castration-resistant PCSCs are AR-PSA- and completely refractory to antiandrogens but remain partially sensitive to inhibitors of BCL-2 and certain kinase. Dr. Rycaj became a junior faculty in 2015, and her lab has been focusing on elucidating how primary tumor microenvironment regulates functional properties of metastatic PCSCs and on developing novel immunotherapeutic strategies to target undifferentiated, therapy-resistant and metastasis-prone PCa cells.

    Abstract

    Androgen deprivation therapy (ADT) is the mainstay treatment for patients with advanced prostate cancer (PCa). Despite an initial response, the majority of patients relapse resulting in castration-resistant prostate cancer (CRPC). Both untreated advanced PCa and CRPC are enriched in phenotypically undifferentiated PCa cell populations that expresses little or no prostate specific antigen (i.e., PSA-/lo). We have demonstrated that the PSA-/lo PCa cell population harbors self-renewing prostate cancer stem cells (PCSCs) that are intrinsically resistant to ADT and can long-term propagate tumors, mediate recurrence, and serve as a cell-of-origin for CRPC (Cell Stem Cell, 2012; Oncotarget, 2015; Clin Cancer Res, 2016; Oncotarget 2016). Consequently, it is important to find therapeutics that can preferentially target these cells. By employing phage display technology, we screened a combinatorial library for peptides that preferentially bind to PSA-/lo LNCaP PCa cells. An initial competitive assay identified the JRM1 peptide that showed slight preferential binding to the PSA-/lo LNCaP cells. With this knowledge, we carried out another screen using an indirect subtraction assay to identify the peptide JRM2, which demonstrated preferential and statistically significant binding to the PSA-/lo LNCaP cells. Fluorophore-conjugated JRM2 could be internalized into cells. When conjugated to a pro-apoptotic peptide, JRM2 specifically inhibited cell proliferation in PSA-/lo PCa cells. Preliminary in vivo studies showed tumor-inhibitory effects of the JRM2-killer peptide conjugates. Our findings demonstrate the feasibility of utilizing novel ligand-directed therapeutics to target undifferentiated (AR-)PSA-/lo CRPC cells.

  • Maintenance of cancer stem cells by microRNA
    Speaker
    Qi en Wang
    The Ohio State University
    USA
    Biography

    Qien Wang is an Associatet Professor in the Department of Radiology and Comprehensive Cancer Center at the Ohio State University. Dr. Wang received his Bachelor Degree in Preventive Medicine in Shanxi Medical College in 1992, and obtained his PhD from Beijing Medical University in 1997 in China. Then, Dr. Wang worked as a Lecturer and Associate Professor at Peking University Medical Center for 4 years. During this time, his research was focused on understanding how gene and environmental exposure interact in carcinogenesis. In 2001, Dr. Wang joined Dr. Altaf Wani’s laboratory at the Ohio State University in the United States of America to study the mechanism of DNA repair as a Research Associate and Research Scientist. Since 2011, Dr. Wang has become a Tenure-track Assistant Professor at the Ohio State University, and was promoted to Associate Professor with Tenure in 2017.

    Abstract

    Cancer stem cells (CSCs) are considered to play a central role in the cancer progression, metastasis and the development of drug resistance. MicroRNAs (miRNAs) have important roles in regulating CSC properties and are considered to be potential therapeutic targets. Diverse aberrantly expressed miRNAs have been reported in ovarian cancer cells. However, there have been few reports about miRNAs that were associated with stemness and progression of ovarian cancer. In this study, miRNA Nanostring profiling analysis was performed to screen crucial miRNAs associated with characteristics and maintenance of CSCs in ovarian cancer. We found that miR-328-3p was remarkably upregulated in ovarian CSCs isolated from both ovarian cancer cell lines and primary ovarian tumors compared to their corresponding bulk cancer cells. We further demonstrated that enforced expression of miR-328-3p in ovarian cancer cell lines expanded the population of ALDH+ cells, enhanced their sphere formation ability, as well as increased their tumorigenicity. While inhibition of miR-328-3p limited the ALDH+ cell population, reduced their sphere formation capacity, and decreased their tumorigenicity. The orthotopic ovarian xenograft assay also demonstrated that inhibition of miR-328-3p impedes tumor growth and metastasis. The mechanistic investigation revealed that repressed ERK1/2 phosphorylation in ovarian CSCs, mainly due to reduced level of reactive oxygen species (ROS), contributes to the enhanced expression of miR-328-3p, and the maintenance of CSCs. Finally, we identified DDB2 as a direct target of miR-328-3p. Given our previous finding that DDB2 is capable of limiting the CSC population in ovarian cancers, we conclude that highly expressed miR-328-3p in ovarian CSCs, probably due to repressed ERK1/2 activity, inhibits DDB2 expression, resulting in the expansion of these CSCs. Thus, targeting miR-328 could be exploited to a novel strategy to eradicate CSCs in ovarian cancer.

  • Targeting Notch4 in ovarian cancer results in decreased number of cancer stem cells and increased survival when used in combination with cisplatin in pre-clinical models
    Speaker
    Elaine Hurt
    MedImmune
    USA
    Biography

    Dr. Elaine Hurt received her PhD in Biochemistry, Molecular Biology and Biophysics from the University of Minnesota in 1999 where she studied estrogen receptor signaling cascades. Dr. Hurt did her post-doctoral studies at the National Institutes of Health in the laboratory of Dr. Louis Staudt elucidating the molecular mechanisms governing therapeutic responses in lymphoma and multiple myeloma patients. In 2010, Dr. Hurt joined MedImmune to lead their cancer stem cell group. Prior to joining MedImmune, Dr. Hurt was a Staff Scientist at the National Cancer Institute, where she focused primarily on identifying and targeting prostate cancer stem cells. In 2014, Dr. Hurt became Adjunct Associate Professor in the Department of Biochemistry and Molecular Biology at the University of Maryland. She is the co-inventor on several patents, has been an invited speaker at numerous conferences, and has published over 50 scientific articles.

    Abstract

    The Notch pathway plays a central role in the regulation of cellular growth and differentiation. There are 4 known receptors and 5 ligands in this pathway. While all receptors have been shown to be important in tumor biology, Notch4 continues to be implicated as a key mediator of cancer stem cell (CSC) biology. CSC-targeted biologics are an important part of a comprehensive oncology therapeutic strategy due to the role of CSCs in tumorigenesis, therapeutic resistance and patient relapse. Targeting this sub-population of cells is anticipated to lead to more durable patient responses. We have developed a human IgG1 antibody that targets the negative regulatory region of the Notch4 receptor, keeping it in an auto-inhibited state. We have determined Notch4 is expressed by CSCs of many solid tumors and is increased by cisplatin, a commonly used chemotherapy. Furthermore, uur anti-Notch4 antibody inhibits ovarian CSC growth in vitro and secondary tumor growth in vivo, consistent with depletion of CSCs. Combination of our anti-Notch4 antibody with cisplatin in ovarian tumor models demonstrates a more durable response than cisplatin alone, as expected with a CSC-combination therapeutic approach. Overall targeting Notch4 with an inhibitory antibody demonstrates superior ability, as compared with other Notch pathway inhibitors, to inhibit CSCs in preclinical models.

  • Metakaryotic cancer stem cells are constitutively resistant to x-rays and chemotherapeutic agents but sensitive to many common drugs: first clinical trial shows effectiveness of a metakaryocide against stem cells in human pancreatic tumors
    Speaker
    William G Thilly
    Massachusetts Institute of Technology
    USA
    Biography

    William G. Thilly, Sc.D. was born in Port Richmond NY, USA and is now Professor of Genetics, Toxicology and Biological Engineering at MIT. With multiple collaborators he and Dr Gostjeva are exploring the bizarre physiology of metakaryotic stem cells, growing them in cell cultures, and devising means to kill them with drugs and protocols expected to be well tolerated in patients.

    Abstract

    After radio- and chemo-therapy human tumors display many dead eukaryotic cells with pyknotic nuclei. But amitotic metakaryotic stem cells with hollow, bell shaped nuclei are unaffected as expected of treatment-resistant cancer stem cells. These same phenomena may be observed in vitro using any of many tumor- or metastasis-derived cell lines the immortality of which is conferred by the presence of amitotic, metakaryotic cancer stem cells. About 5% of human colonic adenocarcinoma-derived HT-29 cells in exponential growth are immortal metakaryotic stem cells that increase by symmetric amitoses and continuously create mortal mitotic eukaryotic cells by asymmetric amitoses. Two assays for agents/conditions specifically toxic to metakaryotic stem cells have been devised: (a.) microscopic recognition of necrotic metakaryotic nuclei and (b.) survival of cells forming large immortal colonies visibly containing metakaryotic stem cells in vitro. X-rays and chemotherapeutic agents (alkylating agents, antimetabolites and mitocides) have been found to kill eukaryotic cells but not metakaryotic cells at doses commonly used in cancer therapy. In contradistinction, we have shown that multiple classes of common drugs are preferentially cytotoxic to metakaryotic stem cells including NSAIDS, antibiotics and drugs used to treat diabetes, hypertension and other medical conditions. Here are reported the first images demonstrating killing of the preponderance of metakaryotic cancer stem cells in a series of pancreatic tumors by an antibiotic metakaryocide in a clinical trial in progress at the Medical College of Wisconsin (Prof. Susan Tsai, M.D, Principle Investigator). Research plans to identify effective protocols for a series of metakaryocidal drugs are outlined..

  • Molecules Targeting Cancer Stem Cells
    Speaker
    Maithili A. Athavale
    Godavari Academy of Science & Technology
    India
    Abstract

    The aim of the present project is to Synthesise novel derivatives of diphylline glycoside of CleistanthinA(SBGB-0001-000) and to screen them for anticancer activity (by MTT ,Soft Agar Assay) and anticancer stem cell activity (by tumorsphere assay)on Breast Cancer cell lines. In all 70 novel derivatives of SBGB-0001-000 were synthesized and screened for anticancer and anticancerstemcell activity.Out of 70,two derivatives namely, SBGB-0001-014 and SBGB-0001-023 exhibited better anticancer and anticancer stem cell activity compared to standard chemotherapeutic drug Cisplatin. Since, Cancer stem cells(CSCs)are subpopulation of cells within the cancer tissues with drug resistance and metastatic properties,these two candidates were further tested for its anticancer stem cell activity on drug(Paclitaxel)resistant population on highly metastatic breast cancer cell lineMDAMB231(with high number of CSCs)compared to standard Chemotherapeutic drug Cisplatin and a target drug therapy Sunitinib.Our sphere assay results indicate that the candidate molecules have better anticancer stem cell potential,inhibiting spheres at 25nM compared to Cisplatin and Sunitinib.”fig1” Briefly,our in-vitro data supports the anticancerstemcell effect of two novel candidates on breast cancer cell lines.Further these candidates do not exhibit any toxic effect on normal cells (peripheral blood lymphocytes)compared to Cisplatin.The molecules show good hepatocyte stability and have been taken further for the precilinal studies like PK-PD,MTD and Xenograft studies.

  • hTERThigh Numb-/low state enriches a castration resistant prostate cancer cell subpopulation with tumor initiating capacity
    Speaker
    Helen He Zhu
    Shanghai Jiao Tong University
    China
    Biography

    Helen He Zhu received her Bachelor Degree from Fudan University, China. She performed her Ph.D. study in Molecular Pathology at School of Medicine, University of California-San Diego and did her postdoctorate training in the Department of Biology , University of California-San Diego. In 2012, Dr. Zhu relocated back to China and started to work as an Associate Professor then Professor in Ren Ji Stem Cell Research Center, Ren Ji Hospital at School of Medicine, Shanghai Jiao Tong University. Her current work focuses on 1) adult tissue stem cells from hematopoietic system and prostate in tissue development and tumorigenesis. 2) roles of prostate cancer stem cells in therapeutic resistance and tumor metastasis. Her publication includes first author and corresponding author papers in Blood, PNAS, Gastroenterology, Clinical Cancer Research, Cancer Research and etc.

    Abstract

    Castration resistant prostate cancer (CRPC) remains one of the most deadly and incurable cancer types worldwide. Tumor cells in CRPC patient samples display tremendous heterogeneity. Cancer stem cells (CSCs) are proposed to be the driving force in cancer progression and recurrence. Identification of the CSC or prostate cancer cell sub-population with greater castration resistance is a key to the development of targeted anti-CRPC treatment strategies. We report that the hTERThigh PCa cells exhibit CSC properties including stem cell associated gene expression signature, long term tumor propagating capacity, and epithelial-to-mensenchymal transition. hTERThigh CSC cells display distinct cell division modes and can undergo both symmetric division and asymmetric division, as compared to hTERT-/low Pca cells. Numb, an evolutionarily conserved cell fate determinant, tends to segregate into the more differentiating daughter cell during symmetric division and asymmetric division of hTERThigh CSC cells. Further investigation revealed that Numb is down-regulated and negatively correlated with PCa advancement. Functionally, Numb exerted an inhibitory role in xenograft prostate tumor growth and CRPC development via suppression of Notch and Hedgehog signaling. Through a Numb promoter based lentiviral reporter system, we were able to separate Numb-/low Pca cells from Numbhigh cells. Numb-/low PCa cells are smaller and quiescent, preferentially express Notch and Hedgehog downstream and stem-cell-associated genes, and are associated with greater resistance to androgen deprivation therapy. Targeting Notch and Hedgehog signaling with inhibitors can effectively deplete the Numb-/low castration resistant PCa cells. Collectively, these findings provide novel insight into cellular and molecular mechanisms for the development of advanced CRPC and to the development of effective anti-CRPC treatment strategies.

  • Drug resistant stem cells: Models for targeted therapy of breast cancer
    Speaker
    Nitin Telang
    Institute for Clinical Neurosciences
    USA
    Biography

    Nitin TELANG earned his Ph.D. degree in 1974 from University of Poona, India, and obtained his post-doctoral training (1976-1985) in the USA at University of Nebraska, American Health Foundation, New York, and Memorial Sloan-Kettering Cancer Center, New York. He served on the faculty of Memorial Sloan-Kettering Cancer Center, Weill-Cornell Medical College, and Strang Cancer Prevention Center, New York (1986-2007). He serves as Director, Cancer Prevention Research Program at Palindrome Liaisons Consultants, New Jersey. Dr. TELANG has published more than 100 peer-reviewed papers and serves on the editorial boards of International Journal of Oncology, Oncology Reports and BMC-Complementary& Alternative Medicine.

    Abstract

    Cancer stem cells represent a subpopulation of the primary cancer that is predominantly characterized by drug resistant phenotypes exhibiting tumorigenic potential. Long-term treatment options lead to emergence of drug resistant cancer stem cells. Relevant models for cancer stem cells facilitate novel experimental approaches that identify efficacy of stem cell targeted therapeutic agents. Experiments in the present study were designed to characterize stem cell models from molecular subtypes of clinical breast cancer.

  • The constitution of Cancer tissues: the properties and implication of cancer stem cells derived from patients’ samples
    Speaker
    Xianming Mo
    West China Hospital of Sichuan University
    China
    Biography

    Dr. Xianming Mo is a professor of internal medicine and acts as Director of Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University. He obtained his medicine degree from North Sichuan Medical College. Then he was trained in pathology and accept Master of Medicine in West China University of Medical Science. After obtaining a PhD degree in Peking Union Medical College, He moved to Humboldt-Universität zu Berlin and then to Medical College of Georgia as postdoctoral fellows. Then, he became junior faculty in Medical College of Georgia and senior scientist in Max Delbruck Center for Molecular Medicine. In 2006, he returned back to West China Hospital.

    Abstract

    The growth of cancers depend on the formation of blood vessels that provide the supply of nutrients and oxygen and the nervous system acts as a crucial part of cancer microenvironment. The angiogenesis and vasculogenesis are essential during cancer progression. Recently, several studies have reported that glioblastoma stem cells are able to give rise to tumor vascular endothelial cells (ECs) and vascular pericytes for tumor vascularization. However, there is no evidence to show that the tumor stem cells from other kinds of tumors including carcinoma produce endothelial cells to constitute the functional blood vessels in cancer. In addition, recent evidences have demonstrated that the stimulation of both cancer growth and metastasis by members of nervous system such as neurons. How the nervous system built in cancer tissues is unknown. We transplanted the cancer stem cells that were isolated from the patients with gastric and colorectal carcinoma into nude mice via subcutaneous and intraperitoneal injections to produce human cancer xenografts. Then the innervations, angiogenesis were examined and the origins of the neural cells and endothelial cells were determined in cancer tissues. A single cancer stem cell from the cancer tissues of human patients was able to generate neurons including sympathetic and parasympathetic cells to take part in the nervous system in cancer tissues. Knocking down the neural generating capabilities of the human cancer stem cell inhibited the growth of tumors. Next, we show that cancer stem cells of the human colorectal carcinoma (CoCSCs) give rise to vascular endothelial cells and compose the vasculatures in cancer tissues. NuMA+ EC incorporated blood vessels were functional. Dependent on the biology of cancer stem cell, we identified small molecules to drive the differentiation of the cancer stem cell for restricted cancer grow. Our data demonstrate that neural cells and endothelial cells originated from human cancer stem cells constitute blood vessels and nerve system for the cancer progression in the cancer tissues. The findings are able to guide the development of therapeutic approaches to restrict cancer.

  • Isolation of cancer stem cells from Cancer of Unknown Primary origin (CUP) and generation of a novel in vivo model of early, spontaneous and multiple metastases by subcutaneous transplantation
    Speaker
    Federica Verginelli
    Candiolo Cancer Institute (Italy)
    Italy
    Biography

    Federica Verginelli has accomplished her PhD in Cellular and Molecular Biology at the Tor Vergata University in Rome (Italy), and a 4-years post-doc at the Montreal Neurological Institute (Canada). She is now research associate at the Candiolo Cancer Institute (Italy). She is author of 10 publications that have been cited 297 times, and her publication H-Index is 8.

    Abstract

    Cancer of unknown primary origin or CUPs, represent 3-5% of all cancers with a very poor prognosis (overall survival: 9 months). Patients display unpredictable and precocious metastatic dissemination in the absence of a clinically detectable primary lesion. Histologically, CUPs display mostly epithelial morphology but, invariably, they lack expression of lineage markers that allow unambiguous identification of the tissue of origin. Today many efforts are aimed to develop new molecular diagnostic tools to predict the primary tissue and guide to a more rational therapeutic choice. However, the aberrant molecular mechanisms underlying CUP pathogenesis are largely obscure. Here, we show for the first time the isolation and the extensive in vitro and in vivo characterization of cancer stem cells isolated from CUPs, as cultures named “agnospheres”. Specifically, agnospheres are able to grow in suspension and in the absence of growth factors, they express well-known stem cell markers and are endowed with self-renewal ability and long term propagation in vitro. They repopulate a tumor when transplanted subcutis in immunocompromised mice at very low number (i.e. as few as 10 cells, stem cells frequency: 5-15%). Most importantly, after subcutaneous transplantation, agnospheres recapitulate the whole metastatic cascade, generating metastases in multiple organs (lung, lymph nodes, thymus...) within a month (estimated metastatic stem cell frequency: 1-2%). For the first time to our knowledge, cancer stem cells have been isolated from CUPs, and phenotypically and functionally characterized. We generated a new cancer stem cell model endowed with extremely high tumor-initiating ability and impressive precocious metastogenic potential in different organs. Agnospheres may represent an unprecedented tool for investigating the molecular mechanisms responsible for the metastatic process in general, and to assess the anti-metastatic effect of approved or new therapeutic compounds.

  • Integrated analyses identify a poor-prognosis subtype of hepatocellular carcinoma regulated by a core microRNA regulatory circuitry
    Speaker
    Jiangwen Zhang
    The University of Hong Kong, Hong Kong
    Hong Kong
    Biography

    Dr. Zhang graduated from Johns Hopkins University with PhD. He has worked at Harvard University Genome Center as Senior System Biologist for years before joining University of Hong Kong in 2013. Dr. Zhang lab has broad interest in genetic and epigenetic regulation in development and diseases. Currently, his lab is focusing on epigenetic regulation of tumorigenesis. His lab employs high through-put ‘omics’ assays and large scale computation to dissect the gene regulatory network and signaling pathways involved in oncogenesis.

    Abstract

    Cancer stem cells (CSCs) cause tumor heterogeneity, relapse, and resistance to therapy. The underpinnings of CSCs remain to be elucidated, especially the underlying gene regulatory network. We here conducted integrated analyses and identified a miRNA-regulatory network defining a stemness subtype with poor-prognosis from TCGA hepatocellular carcinoma (HCC) cohort with independent validations. The poor-prognosis subtype was characterized by the signature expression pattern of CSCs orchestrated by two miRNAs and their mRNA targets that formed a core regulatory circuitry (CRC). Within the CRC, miR483-3p bound a complementary sequence on SOX9 promoter, facilitating the recruitment of RNA polymerase II and STAT3, which was essential for SOX9 transcription activation. SOX9 can further activate SOX4 expression. Both SOX4 and its associated activator lncSOX4 were the direct targets of miR204-5p. SOX4 and miR204-5p formed double-negative feedback loop through mutual inhibition. The expression level of miR204-5p was tightly modulated by miR483-3p, whose promoter was significantly de-methylated in the stemness subtype. Activation of the CRC essential for the self-renewal and maintenance of liver CSCs culminated in downregulation of miR204-5p and upregulation of miR483-3p, SOX9, and SOX4. Functional significance of the CRC for HCC metastasis and drug resistance was further demonstrated with various in vitro and in vivo assays.

Day 2

KEYNOTE SPEAKERS
  • Identification of cancer stem cell (CSC) in its spatial context and immune environment through the application of cognitive and machine learning

    Definiens
    Germany
    Biography

    Dr. Ralf Huss joined Definiens in 2013 and has more than 20 years of training and experience in histopathology and cancer research. Dr. Huss also co-founded the biotech company APCETH. He has published more than 100 papers, and has worked with the Nobel Laureates Rolf Zinkernagel and E. Donnell Thomas.

    Abstract

    The identification of Cancer Stem Cells (CSC) or better “cancer initiating cells (CIC)” as therapeutic targets is of pivotal importance to limit the progression, recurrence and metastasis of cancer. This requires the understanding of the residence of CSC / CIC in their tissue environment with contextual information on their spatial connectivity with many different surrounding structures. Advanced tissue diagnostic including multiplexing immunohistochemistry and the integration of all available data has become key to predict the response to treatment and can be used to target CSC / CIC. With the ability to combine cognitive learning technologies with sophisticated analytics assessing the tumor-forming cells, its environment and immune cells including its spatial relationship, image analysis can identify complex and meaningful signatures that incorporate new knowledge into existing (empirical) wisdom to better predict patient response. Artificial intelligence and machine learning applied to image analysis offer an automated solution using quantitative measurements of unique cellular features to objectively and accurately assess a patient’s tumor composition. The improved and increased use of immunotherapies (alone or in combination) to target CSC / CIC will be a result of the automation of contextual cell identification, cell counting and algorithm application to deal with n-dimensional complexity of different stem cell compartments.

  • Epithelial cell adhesion molecule (EpCAM) as a CSC marker in prostate cancer chemo-/radio-resistance

    University of New South Wales
    Australia
    Biography

    A/Prof Yong Li obtained his PhD degree at University of New South Wales (UNSW) Sudney, Australia in 2000. He became Cancer Research Group leader in 2006, and is an established cancer researcher, with expertise in cancer biomarker discovery, radiation biology, target cancer therapy and cancer metastasis. He was awarded an NHMRC Career Development Fellowship (Level 2) in 2010-2014; and an NHMRC Achievement Award (ranked No.1 in the industry fellow) in 2011. He was promoted to an Associate Professor in the Faculty of Medicine, UNSW since 2011, and a Principal Scientific Officer by the South Eastern Sydney Local Health District (SESLHD) since 2012. A/Prof Li has more than 100 career publications in cancer research area since 1999.

    Abstract

    Prostate cancer (CaP) is the most common cancer in males in Australia which caused more than 3000 deaths in 2015. EpCAM is a transmembrane protein that is expressed at low levels in a variety of human epithelial tissues, but overexpressed in most solid tumors. Our previous study indicated that EpCAM was strongly expressed in metastatic CaP cell lines, primary human CaP tissues and lymph node metastasis and is a biomarker involved in CaP progression, and chemo-/radio-resistance. However, the role of EpCAM in CaP progression and therapeutic resistance is still uncertain. The aim of this study was to investigate the role of EpCAM in CaP progression and chemo-/radio-resistance as well as underlying mechanisms using in vitro CaP cell lines and in vivo mouse models for a potential therapeutic target.

  • Key regulators of symmetrical and asymmetrical division of epithelial cells in prostate development and tumorigenesis

    Shanghai Jiao Tong University
    China
    Biography

    Wei Qiang Gao received his PhD from Columbia University in 1989 and did his post-doctoral re¬search at Columbia University and Rockefeller University. From 1993-2010, he was a Scientist and Senior Scientist at Genentech, Inc.. He then relocated to China to initiate his endowed chair professorship in Shanghai. He has made import¬ant contributions to the fields of neuroscience, stem cells and tumorigenesis. More recently, his group focuses on “cancer research and cancer stem cells”. Dr. Gao has published more than 80 papers as either corresponding or the first author, including Nature, Cell, Science, Neuron, Nature Neuroscience, Nature Communications, Gastro¬enterology, PNAS, J. Neurosci., Stem Cell Reports, etc. and has been granted 48 US patents. He is a scholar of national “Thousand-Talents Program”, the Chief Scientist of 2 program projects from the Ministry of Science and Technology of China and 2 key grants from the National Natural Science Foundation of China. He has served as a reviewer for grant proposals of Wellcome Trust in UK, NIH in US, and NSFC and 36 journals including Nature, Nature Medicine, Nature Cell Biology, Nature

    Abstract

    Although symmetrical and asymmetrical divisions of stem cells are extensively studied in invertebrate and mammalian neural epithelia, their role remains largely unknown in mammalian non-neural epithelial development, regeneration and tumorigenesis. Using basal and luminal cell-specific markers and cell lineage tracing transgenic mice, we report that in developing prostatic epithelia, basal and luminal cells exhibit distinct division modes. While basal cells display both symmetric and asymmetric divisions leading to different cell fates, luminal cells only exhibit symmetrical divisions, producing two luminal cells. Examination of cell division modes in prostate-specific Pten mull mice indicates that while transformed luminal cells can independently produce tumors composed of exclusive luminal cells via symmetrical divisions, transformed basal cells appear to generate cancer through the daughter luminal cells derived from asymmetrical divisions. Cell polarity and correct mitotic spindle positioning are essential for the proper prostate epithelial cell division mode, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. However, whether and how these two epithelial attributes are coordinated in vivo is largely unknown. We report that conditional genetic deletion of E-cadherin, a key component of adherens junctions, in a mouse model results in loss of prostate luminal cell polarity and randomization of spindle orientations. Critically, E-cadherin ablation causes prostatic hyperplasia which progresses to invasive adenocarcinoma. Mechanistically, E-cadherin forms a complex with the cell polarity protein SCRIB and the spindle positioning determinant LGN to link cell polarity and cell division orientation. Collectively, these findings provide direct evidence for the existence of a hierarchy of epithelial cell lineages during prostate development and tumorigenesis and a novel mechanism by which E-cadherin acts an anchor to maintain prostate epithelial division orientation and to prevent tumorigenesis in vivo.

Cancer Stem Cells | Prostate Cancer Stem Cells | Colorectal Cancer Stem Cells | Therapies targeting Cancer Stem Cells | Cancer Genomics & Metabolomics
Chair
  • Allied Academies  Cancer Stem Cells 2018  Chair Speaker  Yong Li, photo
    Yong Li,
    University of New South Wales
    Australia
Co-Chair
Speaker
  • Development of novel miR-129 mimic with enhanced therapeutic potential to eliminate resistant colon cancer stem cells
    Speaker
    Jingfang Ju
    Stony Brook University
    USA
    Biography

    Dr. Jingfang Ju is the Professor in the Department of Pathology at Stony Brook Medicine/Stony Brook University. Dr. Ju received his BS degree from the Northeastern University and Ph.D. in molecular biology and biochemistry at the University of Southern California. He completed his post-doctoral research fellowship at Yale Cancer Center, Yale University. Previously Dr. Ju has served as the Senior Scientist and Team Leader of high throughput genomics at a biopharmaceutical company, CuraGen Corporation in Connecticut.

    Abstract

    Treatment of advanced stage colorectal cancer remains a clinical challenge associated with resistance to fluoropyrimidine based chemotherapy. There is an urgent need to discover and develop new strategies to enhance treatment efficacy in order to improve outcomes for these patients. Non-coding microRNAs (miRNAs) have important functions as oncogenes or tumor suppressor genes in the regulation of cancer development and progression. Recently, miRNAs have emerged as potential therapeutic options. We have identified miR-129 as tumor suppressor miRNA and potential therapeutic candidate in colorectal cancer. The expression of miR-129 expression is progressively lost in colorectal cancer patients and is an important regulator of apoptosis through the targeting of genes such as BCL-2. miR-129 was also found to enhance 5-flurouracil (5-FU) cytotoxicity in vitro and in vivo. To further developing miR-129 based novel therapeutics in colorectal cancer, we have designed a modified version of miR-129 to enhance stability and efficacy. The miR-129 mimic is significantly more potent in inhibiting proliferation of a panel of colon cancer cell lines than the native miR-129 precursor. The miR-129 mimic induces profound cell cycle arrest at the G1/S checkpoint. We also demonstrated that the miR-129 mimic retains its target specificity to BCL-2, TS and E2F3 as same as the native miR-129 precursor. More importantly, the miR-129 mimic can eliminate resistant colon cancer stem cells. The therapeutic potential of miR-129 was demonstrated in vivo mouse colon tumor models as a potent inhibitor of tumor growth and metastasis. As a result, miR-129 mimic has a great potential to be further developed as a novel therapeutic drug for treatment of advanced colorectal cancer.

  • Role of miRNAs and YAP in the promotion of colorectal cancer stem cell self-renewal by the tight junction protein claudin-2.
    Speaker
    Frederic Hollande
    The University of Melbourne, Australia
    Australia
    Biography

    Frederic Hollande completed his PhD in 1994 at the University of Montpellier, France. He worked as a post-doctoral research fellow at the Ludwig Institute for Cancer Research and the University of Melbourne, and was recruited as a Research Fellow by the French National Centre for Scientific Research (CNRS) in 1996. Frederic became Group Leader in 2000 and Head of the Oncology Research Department at the Institute of Functional Genomics (IGF) of Montpellier in 2011. In 2007, he co-founded a biotech company (colon cancer therapeutics) and was the joint-scientific director of until 2011. Frederic has been an Associate Professor in the Department of Pathology at the University of Melbourne since September 2012. His laboratory is located at the new purpose-built Victorian Comprehensive Cancer Centre in Melbourne. His research interest lies in the study of tumour heterogeneity and the regulation of cancer stem cells in colorectal and other cancers.

    Abstract

    Colorectal cancer (CRC) is the third most lethal cancer worldwide, often due to post-treatment recurrence driven by a subpopulation of Cancer Stem Cells (CSCs). The tight junction (TJ) protein claudin-2 is overexpressed in human CRC, where it enhances cell proliferation, colony formation and chemoresistance in vitro. While several of these biological processes are features of the CSC phenotype, a putative role for claudin-2 in the regulation of these had hitherto not been explored. Here, we identify that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence-free survival after 5-FU-based chemotherapy, an outcome in which CSCs play an instrumental role. Using overexpression and/or down-regulation models in patient-derived organoids, primary cells and cell lines, we show that claudin-2 promoted CRC self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDH High CSCs and increased their proportion in CRC cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSCs towards the ALDH High phenotype. Using Next Generation Sequencing in ALDH High cells, we establish that claudin-2 regulated the expression of several microRNAs known to control stem cell signalling. We demonstrate that, among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2. We also found that the enhancement of self-renewal by claudin-2 required the activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of the TJ protein claudin-2 promotes self-renewal within CRC stem-like cells, suggesting a potential role for this protein as a therapeutic target in CRC.

  • Therapeutic Stress Induced Cellular Plasticity: A Possible New Mechanisms of Therapeutic Resistance in Glioblastoma
    Speaker
    Atique Ahmed
    Northwestern University
    USA
    Biography

    Atique U. Ahmed currently appointed as Assistant Professor of Cancer Biology and member of the Lurie Comprehensive Cancer Center, Northwestern University, Chicago IL USA. He received his Ph.D. in Molecular Medicine from Mayo Graduate School, USA. He has over 60 publications that have been cited over 2500 times, and his/her publication H-index is 31 and has been American Cancer Society Scholar.

    Abstract

    Glioma stem cells (GSCs), a rare population of cancer cells capable of self-renewal, are known to underlie therapeutic resistance in glioblastoma (GBM), the most common and aggressive adult primary brain tumor. Previously, we have shown that the anti-glioma chemotherapy temozolomide (TMZ) initiates remarkable plasticity in glioma cells and promotes the conversion of differentiated glioma cells to therapy resistant GSCs. Our initial investigation indicated that Polycomb group protein EZH2 is critical for this therapy-induced cellular plasticity. Genome-wide chromatin immunoprecipitation (ChIP) in parallel with DNA sequencing analysis (ChIP-seq) revealed 1449 distinct regions enriched for EZH2 binding, specifically at the promoter regions of several key genes including PTPRT, CDK5R2, and Siglec6. Gene expression microarray analysis showed that this binding decreased cognate gene expression in an effort to activate the master transcription factor STAT3, a key molecular factor in promoting the GSC niche. To further investigate this plasticity-based adaptation, we next performed histone 3 lysine 27 acetylation (H3K27ac) enrichment analysis in order to mark the transcriptionally active chromatin state on a genome wide scale before and after exposure to TMZ. A significant number of distal H3K27ac peaks were detected only after chemo- (n = 452) and radiotherapy (n= 1029), indicating that H3K27ac was modified by anti-glioma therapies in a locus-specific manner. Furthermore, a de novo motif analysis identified the homeobox TF binding motif (p=0.025) enriched within the H3K27ac peak surrounding sequences during therapy. By combining the transcriptome analysis from patientderived xenograft models and GBM patient data (TCGA) with the H3K27ac enriched marks, we have identified several novel homeobox transcription factors, which may contribute to therapyinduced cellular plasticity and adaptation response. These findings provide new insight into the molecular mechanisms by which epigenetic plasticity regulates the GSC niche and may improve our understanding of how GBM cells resist current treatment modalities.

  • Replication stress response in CSCs: molecular mechanisms and therapeutic implication
    Speaker
    Ilio Vitale
    The University of Rome Tor Vergata
    Italy
    Biography

    Dr Ilio Vitale received his Ph.D. in 2006 for the molecular characterization of mitotic catastrophe. During his 6-years post-doc in France he investigated the role of aneuploidy/tetraploidy in tumorigenesis uncovering surveillance mechanisms surveying cell ploidy (EMBOJ 2010, Science 2012). He is currently Group Leader and Adjunct Professor in Neuobiology at the University of Rome “Tor Vergata” working on the link between CSCs, chromosomal instability, and tumor immunity. His group recently identified a novel strategy for the depletion of CSCs based on CHK1 inhibition (Gut 2017, Mol Cell 2017). He is the Executive Editor of Molecular & Cellular Oncology, Subject Editor in the Reference Module in Life Sciences and served as Editor for several books. He received the Young Scientist Award from the European Environmental Mutagenesis Society (2013). He is author of >100 ISI papers (including Science, Nat Med, Nat Rev Mol Cell Biol., Nat Cell Biol). “h” index: 34.

    Abstract

    Cancer stem cells (CSCs) are subpopulations of multipotent SCs responsible for the initiation, long-term clonal maintenance, growth and spreading of most human neoplasms, including colorectal cancer (CRC). CSCs reportedly share with embryonic and adult SCs a very robust DNA damage response (DDR), which favors their survival and drives the resistance to endogenous and exogenous genotoxins. Taking advantage of a panel of CRC patient-derived tumorspheres enriched for CSCs (CRC-SCs), we demonstrated that CSCs have high, although heterogeneous, levels of replication stress (RS). By performing genetic and cytogenetic analyses, we provided evidence that RS in CRC-SCs is boosted endogenously by p53 deficiency and the presence of supernumerary chromosomes. We also elucidated the tight, but plastic and multipronged RS response put in place by CSCs to set the threshold of and ensure tolerability to RS, which involves CHK1, PARP and some components of the homologous recombination repair. Of relevance for cancer therapy, we showed that such a robust and efficient response confers to replication-stressed CSCs elevated dependency on specific component(s) such as CHK1. Nonetheless, the redundancy and rewiring potential of RS response also favors the acquisition of resistance to RS-modulating and DNA-damaging regimens. Driven by this paradoxical evidence and based on the levels of RS at baseline, we designed dedicated RS response-targeting strategies with long-term CSC depleting effectiveness.

  • DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression
    Speaker
    Thierry Virolle
    Institut de Biologie Valrose- Ibv
    France
    Biography

    Thierry Virolle is a Research Director (permanent position) at Institut National de la Santé et de la Recherche Médicale (INSERM), Head of the Team Cancer Stem Cell Plasticity and Functional intra-tumor Heterogeneity at the Institute of Biologie Valrose (iBV). He is Co-Founder of the French National Sud Cancer Stem Cell Network, SUNRiSE dedicated to the study of cancer stem cell.

    Abstract

    Glioblastomas (GBM) are lethal primitive brain tumours characterized by a strong intra-tumour heterogeneity. We observed in GBM tissues the coexistence of functionally divergent micro-territories either enriched in more differentiated and non-mitotic cells or in mitotic undifferentiated OLIG2 positive cells while sharing similar genomic abnormalities. Understanding the formation of such functionally divergent micro-territories in glioblastomas (GBM) is essential to comprehend GBM biogenesis, plasticity and to develop therapies. Here we report an unexpected anti-proliferative role of beta-catenin in non-mitotic differentiated GBM cells. By cell type specific stimulation of miR-302, which directly represses cyclin D1 and stemness features, beta-catenin is capable to change its known proliferative function. Nuclear beta-catenin accumulation in non-mitotic cells is due to a feed forward mechanism between DOCK4 and beta-catenin, allowed by increased GSK3-beta activity. DOCK4 over expression suppresses selfrenewal and tumorigenicity of GBM stem-like cells. Accordingly in the frame of GBM median of survival, increased level of DOCK4 predicts improved patient survival.

  • CD44 variant 6 (CD44v6) as a cancer stem cell biomarker in prostate cancer progression and chemo-/radio-resistance
    Speaker
    Jie Ni
    University of New South Wales
    Australia
    Biography

    Jie (Kevin) Ni is a Scientific Officer and Hospital Scientist in Department of Radiation Oncology, Cancer Services at St George Hospital, Sydney and Conjoint Lecturer in St George and Sutherland Clinical School, Faculty of Medicine at UNSW Sydney, Australia. Dr Ni obtained his M.D. and B.A. degrees from China in 2011 as an outstanding graduate and national scholarship awardee and completed his Ph.D. in Faculty of Medicine at UNSW Sydney in 2015. During his PhD candidature he was awarded Prostate and Breast Cancer Foundation Scholarship from 2012-2015, and Outstanding Self-Financed Students Abroad Award of China in 2013. The nature of the degrees has equipped Dr Ni with a strong background of medical practice, and has involved a great deal of independent basic, translational and clinical research. He has 19 publications (6 as the first-author, 2 invited reviews) on peer-reviewed journals on novel therapeutic modalities and targets on prostate, ovarian, cervical and breast cancers. Dr Ni's publications have been cited more than 480 times with a Scopus h-index of 11 and he constantly publishes in top-ranking journals including Theranostics, Oncotarget, Cell Death and Disease, Prostate, and Cancer Metastasis Reviews. Dr Ni’s has been an executive committee member of the Australian Association for Chinese Biomedical Scientists since 2011, a member of American Association for Cancer Research since 2012, European Association for Cancer Research since 2017 and European Society for Medical Oncology since 2017. Dr Ni is currently co-supervising and mentoring PhD students, ILP students and visiting research fellows, and has served as a reviewer for numerous journals and universities.

    Abstract

    Prostate cancer (CaP) is the most common cancer in men in western countries, accounting for estimated 161,360 new cases and 26,730 deaths in the US in 2017. Chemo-/radio-resistance is an important reason for CaP progression and metastasis. CD44 is a well-documented cancer stem cell (CSC) biomarker, and one of its variants, CD44 variant 6 (CD44v6) is closely associated with aggressive behaviour and correlates with poor prognosis in a variety of human cancers. Our previous study has demonstrated increased expressions of CD44v6 in metastatic CaP cell lines and human CaP tissues which was associated with CaP progression and chemo-/radio-resistance in vitro. However, the role of CD44v6 in CaP progression and therapeutic resistance in vivo is still uncertain. The aim of this study was to investigate the role of CD44v6 in CaP development and chemo-/radio-resistance as well as underlying pathways in vivo, and find whether it is a suitable therapeutic target for CaP therapy.

  • NFATc2-SOX2 coupling supports cancer stem cells and mediates drug resistance of lung adenocarcinoma
    Speaker
    Maria Wong
    Chinese University of Hong Kong, Hong Kong
    Hong Kong
    Biography

    Maria Pik Wong is currently working as a professor at the Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR China.

    Abstract

    Cancer stem cells (CSC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of CSC induction or maintenance in human lung cancer is not fully understood. Calcium signaling integrates exogenous and endogenous stress stimuli leading to cellular responses that overlap with cancer functions. We investigated the role and mechanisms of the calcium pathway transcription factor NFATc2 in lung CSC, and found NFATc2 enhanced CSC phenotypes including tumorspheres, motility, tumorigenesis, as well as in vitro and in vivo responses of lung cancer cells to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation and adverse patient survivals. Since pluripotency factors can modulate widespread transcriptomic changes through epigenetic reprograming, we investigated their candidacy as mediators of NFATc2 on CSC regulation. We found NFATc2 transactivated SOX2 through a novel 3’ enhancer locus, while inhibiting SOX2 in cancer cells that overexpressed NFATc2 led to suppressed CSC functions. Targeting NFATc2-SOX2 coupling provides a novel approach for the long term treatment of lung cancer through TIC elimination.

  • Targeting the multidrug transporter Patched potentiates chemotherapy efficiency in vitro and in vivo
    Biography

    Isabelle Mus-Veteau is currently working at the Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Université Côte d'Azur, France

    Abstract

    One of the crucial challenges in the clinical management of cancer is the resistance to chemotherapeutics. We recently demonstrated that the Hedgehog receptor Patched, which is overexpressed in many recurrent and metastatic cancers, is a multidrug transporter for chemotherapeutic agents such as doxorubicin. The present study provides evidences that Patched is expressed in adrenocortical carcinoma (ACC) patients, and is a major player of the doxorubicin efflux and the doxorubicin resistance in the human ACC cell line H295R. We discovered a drug-like molecule which inhibits the doxorubicin efflux activity of Patched, enhances the cytotoxic, pro-apoptotic, antiproliferative and anticlonogenic effects of doxorubicin on ACC cells which endogenously overexpress Patched, and thereby mitigates the resistance of these cancer cells to doxorubicin. Moreover, we report that in mice the combination of this molecule with doxorubicin prevents the development of xenografted ACC tumors more efficiently than doxorubicin alone by enhancing the accumulation of doxorubicin specifically in tumors without obvious undesirable side effect. Our results suggest that the use of an inhibitor of Patched drug efflux in combination with doxorubicin could be a promising therapeutic option for adrenocortical carcinoma, and most likely also for other Patched-expressing cancers

Day 3

Cancer Stem Cells and Haematopoietic Stem Cells in Leukaemia | Therapies targeting Cancer Stem Cells | Cancer Stem Cells in Brain Gliomas | Neuro Oncology
Chair
  • Allied Academies  Cancer Stem Cells 2018  Chair Speaker  Yong Li, photo
    Yong Li,
    University of New South Wales
    Australia
Co-Chair
Speaker
  • Testing the resilience of cancer stem cells to magnetic hyperthermia and heat-mediated drug delivery
    Speaker
    Soraia Fernandes
    Italian Institute of Technology
    Italy
    Biography

    Soraia Fernandes has received her Ph.D. degree, in Natural Sciences from the University of Regensburg (Germany) and in Chemistry and Materials Science and Technologies from the University of Genoa (Italy), in 2016. She is currently a Postdoctoral associate in the research group of Dr. Teresa Pellegrino at the Italian Institute of Technology (Italy). Her research focus is the biological assessment of magnetic nanoparticles as heat mediators and/or drug delivery systems for the development of an effective treatment against cancer.

    Abstract

    Cancer stem cells (CSCs) are well known for being responsible for tumor regression and metastasis. In particular, quiescent CSCs, kept at a non-proliferating state, have been identified in many human malignancies as the subcellular tumor type that causes resistance to current chemotherapy. Available chemotherapeutics attack the cells by blocking their division and replication, resulting ineffective for the eradication of those cells that rarely divide. Therefore, an efficient cancer therapy must act also on quiescent CSC in order to avoid tumor relapse. In this study, we have investigated the potential of magnetic hyperthermia in combination with a chemotherapeutic agent (Doxorubicin) to eliminate colorectal CSCs (CR-CSCs), expressing high levels of CD44v6 markers, withdrawn from patient. Preliminary results from our research suggest that these cells are sensitive to heat under certain magnetic hyperthermia conditions. Therefore, we have been exploiting the use of magnetic iron oxide nanocubes (IONCs) developed in our group, loaded or not with doxorubicin, to study their effect on CR-CSCs. We hypothesize that under the severe effect caused by the heat generated by the IONCs, which kills most of the cell population, quiescent CSCs will struggle to survive, thus starting to divide and being more susceptible to the action of the doxorubicin released from the nanocubes. The obtained results using this cell model revealed that the combined effect of doxorubicin and heat might lead to more efficient CSCs elimination, encouraging the use of such smart nanoplatforms for further studies.

  • CDK6-mediated Suppression of CD25 is Required for Self-renewal of LSCs
    Speaker
    Miaofen Hu,
    Tufts Medical Center, USA
    USA
    Biography

    Miaofen G Hu has completed his PhD from Boston University School of Medicine and postdoctoral studies from Harvard University School of Medicine. She has been Assistant Professor at TUFTS medical Center since 2011. She has published 24 papers in reputed journals. Her most significant research accomplishments thus far include creating a CDK6 mouse model, discovering the role of CDK6 as a common mediator of Notch1 and AKT1 signaling pathways, establishing the potential therapeutic role of CDK6 in T cell malignance, revealing the function of CDK6 kinase activity in negatively regulating the conversion of fat-storing cells into fat-burning cells.

    Abstract

    Despite recent advances in chemotherapy, relapse is frequent, possibly because the available therapies do not eradicate the cells that initiate and sustain the disease in vivo, so-called leukemia stem cells (LSCs). Cyclin-dependent kinase 6 (CDK6) regulates cell cycle progression and modulates differentiation of certain cells. It is predominantly expressed in hematopoietic cells and over-expressed in human T-ALL/LBL. To clarify the role of CDK6 in cell cycle control and tumorigenesis, I have generated mice with targeted mutations in Cdk6. These “knock-in” alleles generate hyperactive or inactive kinase subunits that may better mimic hyperactivation of CDK6 in tumor cells or model pharmaceutical inhibition of CDK6, respectively. We have found that CDK6 is required for initiation and maintenance of T-ALL leukemia and lymphomagenesis induced by constitutively active Notch/Myr-AKT. Pharmacologic inhibition of CDK6 kinase induces CD25 expression, cell cycle arrest, and apoptosis in mouse and human T-ALL. Ablation of Cd25 in a K43M background restores Notch-induced T-leukemogenesis, with disease that is resistant to CDK6 inhibitors in vivo. Moreover, loss of Cd25 in a K43M background restore the ability of LSCs to self-renew. These data support a model whereby CDK6-mediated suppression of CD25 is required for initiation of T-ALL by activated Notch1, and CD25 induction mediates the therapeutic response to CDK6 inhibition in established T-ALL. These results both validate CDK6 as a molecular target for therapy of this subset of T-ALL and suggest that CD25 expression could serve as a biomarker for responsiveness of T-ALL to CDK4/6 inhibitor therapy.

  • Magnetic Nanocrystals and magnetic hyperthermia to tackle cancer stem cells
    Speaker
    Teresa Pellegrino
    Italian Institute of Technology
    Italy
    Biography

    Teresa Pellegrino has received her PhD at the age of 30 years in Chemical synthesis and nanoscience in 2005 from the University of Bari, Italy. Since 2014 she is tenured team leader of the group of “Nanomaterials for Biomedical Applications” at the Italian Institute of Technology, Genoa, Italy. Her current research interests focus on the development of inorganic nanostructures for drug delivery, magnetic hyperthermia, photo-thermal treatment and radiotherapy applications. She is coauthor of 112 publications in the field of nanoscience, nanomedicine and drug delivery systems that have been cited more than 10000 times, and her H-index is 44.

    Abstract

    The use of heat to reduce tumor mass is very ancient. Nowadays, there are several techniques that allow to precisely focalize the heat in very specific body regions resulting in treatments that are more efficient and minimize side effects. Magnetic Nanoparticles can act as heat mediators under external magnetic activation in the so-called magnetic hyperthermia. The field of magnetic hyperthermia has received a renewed interest since the colloidal syntheses by non-hydrolytic methods have revealed several merits over conventional wet chemical hydrolytic processes in terms of controlled size, size distribution and crystallinity. All these parameters together with nanoparticles solubility and state of aggregation can affect structural and magnetic properties of nanomaterials and thus their heat performance. I will first focus on our recent progress on iron-based nanoparticles as heat mediators. Then, I will show our ongoing studies aiming at correlate heat effects on cancer stem cells. I will also report about in vitro hyperthermia experiments on primary tumor cells to relate nanoparticle geometry to changes of magnetic hyperthermia performances in tumor cell. Finally, I will show our preliminary in vivo studies performed with the aim to combine magnetic hyperthermia and heat-mediated drug release.

  • Neurotrophins receptors: new aggressiveness markers in glioblastoma?
    Speaker
    Barbara Bessette
    Université de Limoges, France
    France
    Biography

    Barbara Bessette received her Ph.D. degree in Neuroscience and oncology from the University of Limoges, France in 2006. She worked one year in Paris on pediatric brain tumors and the characterization of cancer stem cells in these tumors. She followed her post-doctoral experience by collaborating and working for 3 years on GLIADYS project with IDD-Biotech (International Drug Development Biotech), specialized in monoclonal antibodies production in Lyon, France. The project consisted to develop new therapeutics for gliomas. During this project, she develops partner relationship with Oncomedics (CRO specialized in Individualized tumor response tests). She is currently a full-time assistant Professor at the University of Limoges in the Department of Physiology and she leads research into HCP-CAPTur team. Her current research activity focuses on cancer stem cells in glioblastoma and the role of neuropeptides in their therapeutic resistance capacity. One of the workpackages leaders in SUMCASTEC (H2020 European Project) she participates to determine cancer stem cell electromagnetic signature in glioblastoma and medulloblastoma.

    Abstract

    Glioblastoma (GBM) is the worst brain tumor with therapeutic resistance and recurrence due to its strong cell heterogeneity, which relies on cancer stem-like cells’ presence. Tumor aggressiveness is associated to cancer cell adaptation to their environment: autophagy process enhancement, the increase of growth factors signaling such as neurotrophins (TrkB/BNNF and TrkC/NT3), microenvironment modulation by mesenchymal stem cells (MSC) The high level of hypoxia commonly encountered in GBM is counterbalanced by the tumor autophagic capability and growth factors signaling activation. We demonstrated that an increase of autophagy precedes TrkC/NT3 pathway activation in GBM cells. Enhancement of both TrkC and NT-3 followed by the increase of p38MAPK phosphorylation, suggesting the occurrence of a survival loop that was also underlined in patient’s tumors. However, the double inhibition of autophagy and TrkC signaling was the only one able to bring cells apoptosis. The ability of cancer cells, to shape tumor environment through exosomes release could explain the spreading of “therapeutic resistance” to neighboring cells. The “stemness” properties loss showed in YKL-40-silenced cells can be reversed by TrkB-containing exosomes provide by native cells. This process contributes to restore cell proliferation and to promote endothelial cell activation. In a xenograft model, TrkB-depleted exosomes from YKL-40-silenced cells inhibits tumor growth in vivo. Our recent works showed changes in MSC behavior “aggressiveness” by the GBM cell “secretion”, following irradiations suggesting a putative link with neurotrophin receptor. Our data suggest that neurotrophin and their receptors could be considered as new relevant diagnosis biomarkers and potential therapeutic targets in glioblastoma.

  • SETMAR in Glioblastoma: Splice variants and feedback network in controlling target genes expression
    Speaker
    Corinne Augé-Gouillou
    University of Tours, France
    France
    Biography

    Corinne AUGE GOUILLOU has completed her PhD at the Pasteur Institute of Paris in 1993 and postdoctoral studies from Tours University. She has been leading her research team for over 15 years and published more than 25 papers in reputed journals. She is very strongly involved in teaching and pedagogy, especially for young students who arrive at the University. She has been serving as a referee for many journals, and led a French network dedicated to mobile DNA.

    Abstract

    SETMAR is a chimeric protein, acting as a house-kipping genome guardian in healthy cells. In a recent work [i], we demonstrate that SETMAR expression increases in GBM where different splice variants are produced depending on the stage of the cells: stem cells express a small hyper-stable SETMAR (sm-SETMAR) whereas differentiated cells express a large form known as the “regular” SETMAR enzyme (r-SETMAR). The only difference between both SETMAR proteins originates from the lack of the SET domain on the sm-SETMAR, due to exon-exclusion during pre-mRNA maturation. As a result sm-SETMAR is devoid of any methyl-transferase activity, preventing chromatin modifications and regulations usually assign to r-SETMAR. In contrast, both proteins are still able to promote DNA repair by NHEJ, albeit sm-SETMAR is less effective. Our current works hypothesis that sm-SETMAR may contribute to confer cancer stem sells properties of chimio- and radio-resistance, in addition to alter their normal epigenetic profile. Because SETMAR originates from a mobile genetic element, the human genome contains of thousands of SETMAR DNA binding sites that are in fact fossils of the original transposon. They together constitute a regulatory network. The characterization of target genes differentially regulated by the one or other one of the SETMAR proteins through this network during GBM biogenesis is under progress.

  • TGF-? signaling is a novel therapeutic target for treating metastatic cancers acquired by EMT and cancer stemness
    Speaker
    Seong -Jin Kim
    Seoul National University, Korea
    South Korea
    Biography

    Seong -Jin Kim is currently working as a professor at the PrecisionMedicine Research Center at the Advanced Institute of Convergence Technology, Seoul National University, Korea.

    Abstract

    TGF-? is a multifunctional cytokine involved in diverse cellular functions, including cell growthandimmune responses.TGF-? signaling has emerged as a key architect of themicroenvironmentin poor-prognosis cancers. Disseminatedtumorcells show a strong dependency on aTGF-?-activated stroma during the establishment and subsequent expansion of metastasis.TGF-? also has a positive role on the cancer stem cell (CSC) population promoting or sustaining stemness of the pool of CSCs in diverse types of malignancy.Since TGF-? signaling is dysregulatedin most of humancancers, thus affecting the overall progression to malignancy, TGF-? signaling has been considered a potentially novel therapeutic targetfor treating resistance acquired by EMT.In the TGF-? signaling pathway, TGF-? receptor I kinase inhibitors have shown promise in blocking the TGF-?-mediated tumor progression and metastasis, and enhancing antitumor immunity in nonclinical animal models.Vactosertib, a TGF-? receptor I kinase inhibitor, has shown significant preclinical antitumor efficacy in a range of in vivo metastatic and orthotopic xenograft models and has completed phase 1 clinical trials in USA. Recent molecular classification of gastrointestinal cancer has identified a poor-prognosis transcriptional subtype associated with mesenchymal traits and genes upregulated by TGF-? in stromal cells are robust predictorsof cancer recurrence and metastasis. This observation warrants the development of anti-TGF-? therapies for the treatment of poor-prognosis cancers with TGF-?response signature.

  • Inhibitor of apoptosis proteins determine glioblastomas stem-like cells fate in an oxygen-dependent manner
    Speaker
    Aurélie Tchoghandjian
    Axe Marseille Université, France
    France
    Biography

    Aurélie Tchoghandjian currently works in the INP – Institut de Neurophysiopathologie, Axe Marseille Université, France.

    Abstract

    Smac mimetics (SMs) are inhibitor of apoptosis proteins (IAPs) antagonists. In glioblastomas (GBs), SMs can trigger apoptotic and non-apoptotic processes1,2,3. As GBs are highly hypoxic, we investigated SM GDC-0152 effect in GB stem-like cells according to oxygen level. We showed that in an environment rich in oxygen (normoxia), GDC-0152 induced loss of stem-cell properties. Unexpectedly, in an environment deprived of oxygen (hypoxia), it triggered apoptosis and decreased cell proliferation. Analysis of Serine-Threonine Kinases activation upon GDC-0152 treatment revealed involvement of different signaling pathways according to oxygen level. In normoxia, NF-?B pathway was activated and in hypoxia, GDC-0152 efficacy was ATR- and TNF?-dependent. This work shows that GDC-0152 triggers anti-tumoral effects whatever the tumoral oxygen pressure, therefore SMs appear as promising molecules in GBs treatment.

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