Investigating L1CAM-dependent stem cell regeneration in metastasis

研究转移中 L1CAM 依赖性干细胞再生

基本信息

批准号：
10227184
负责人：
Karuna Ganesh
金额：
$ 25.68万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-13 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227184
关键词：
Advisory Committees Alleles Anoikis Antibodies Award Biochemical Biochemistry Cancer Etiology Cancer Patient Carcinoma Cell Adhesion Molecules Cell Cycle Cell Differentiation process Cells Cessation of life Chromatin Clinical Colitis Colon Colorectal Colorectal Cancer Data Dependence Development Development Plans Disease Outbreaks Disseminated Malignant Neoplasm Dissociation Distant Distant Metastasis Drug Targeting E-Cadherin Educational workshop Enhancers Environment Epithelial Epithelial Attachment Epithelial Cells Foundations Funding Gene Expression Genetic Engineering Genetic Transcription Genetically Engineered Mouse Gland Goals Grant Homeostasis Human In Vitro Injections Injury International Intestinal Mucosa Intestinal Neoplasms Investigation KRAS2 gene Knock-out LGR5 gene Laboratories Liver Maintenance Medical Oncologist Medical Oncology Membrane Memorial Sloan-Kettering Cancer Center Mentors Metastatic Neoplasm to the Liver Modeling Molecular Molecular Target Mus Mutation NRCAM gene Natural regeneration Neoplasm Metastasis Neural Cell Adhesion Molecule L1 Oncogenic Organ Organoids Patient-Focused Outcomes Patients Phenotype Physicians Positioning Attribute Process Relapse Research Research Personnel Research Project Grants Resistance Role Sampling Scientist Signal Pathway Structure Structure of splenic vein TP53 gene Tail Therapeutic Time Tissues Training Transcription Repressor Transcriptional Regulation Transplantation Tumor Cell Invasion Work adenoma base cancer cell career career development clinically relevant effective therapy epigenetic regulation experience gastrointestinal improved in vivo in vivo Model inhibitor/antagonist innovation instructor knock-down lung metastatic mRNA Expression metastatic colorectal mouse model mutant neoplastic novel novel strategies oncology service predicting response prevent public health relevance rectal regenerative restoration self-renewal stem cell self renewal stem cells stem-like cell targeted biomarker therapeutic development therapy outcome therapy resistant tissue repair trait transcriptomics translational cancer research transplant model tumor tumor initiation tumor progression

项目摘要

PROJECT SUMMARY Metastatic cancers invariably relapse due to the emergence of resistant subclones that are capable of self- renewal, slow cell-cycling, tumor re-initiation and therapy resistance, termed metastasis stem cells (MetSCs). Yet the molecular mechanisms MetSCs employ for survival and regrowth are poorly understood. Preliminary data described in this proposal identify the cell-adhesion molecule cell adhesion molecule L1 (L1CAM) as a critical target for suppressing metastatic relapse. Employing novel patient-derived organoid models of therapy- resistant colorectal cancer (CRC) liver metastases, L1CAM+ cells in patient tumors are shown to selectively regenerate organoids ex vivo. L1CAM is required for the regeneration of organoids in vitro, and the mouse colon epithelium after colitis injury in vivo. Disruption of cell-cell contact in intact epithelial structures is necessary and sufficient for L1CAM induction, with expression diminishing over time as the epithelium is regenerated. We hypothesize that epithelial disintegrity induces L1CAM expression, which is required for the survival and regrowth of cancer cells during invasion, metastasis and following therapy. The mechanisms that induce L1CAM dependency during tumor progression will be defined (1) using patient-derived organoid models of metastatic CRC to define the transcriptional regulation of L1CAM downstream of epithelial junction dissociation and (2) using genetically engineered mouse models, cutting-edge organoid-derived orthotopic rectal transplantation, and orthotopic liver and lung metastatic models in vivo to determine the role of L1CAM in tumor initiation, local invasion, metastatic colonization and maintenance. The proposed investigations will delineate signaling pathways by which tumor dissemination induces phenotypic plasticity and the emergence of metastatic traits, and will pave the way for L1CAM-targeting drugs that inhibit metastasis regeneration. The applicant, Dr. Karuna Ganesh, an Instructor in the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center (MSKCC), has delineated a 5-year career plan that builds upon her research background in biochemistry and clinical training in medical oncology. This project will provide the ideal training for Dr. Ganesh in using clinically representative, state-of-the-art patient-derived organoid and mouse models to dissect the transcriptional and epigenetic regulation of metastasis. Dr. Ganesh will be mentored by Dr. Joan Massagué, an internationally renowned expert in metastasis with a strong track record of training successful independent physician scientists. The candidate's career development plan includes coursework, workshops, mentoring from an interdisciplinary advisory committee comprising distinguished basic scientists and medical oncologists, and research experience in the outstanding institutional environment of MSKCC, a center of excellence in translational cancer research. Successful completion of the research project will lead to new approaches for treating patients with metastatic cancer and will provide the foundation for Dr. Ganesh to transition to a position as an independent investigator with her own laboratory and R01 funding.

项目摘要由于能够自我的抗性亚克隆的出现，转移性癌总是可以缓解更新，缓慢的细胞循环，肿瘤再生和耐药性，称为转移干细胞（METSC）。然而，对生存和遗憾的雇员的分子机制知之甚少。初步的该提案中描述的数据确定细胞粘附分子细胞粘附分子L1（L1CAM）为A 抑制转移继电器的关键目标。采用新型的患者衍生的类器官模型 - 抗性结直肠癌（CRC）肝转移，患者肿瘤中的L1CAM+细胞有选择地再生器官在体内。 L1CAM在体外重生需要L1CAM，而小鼠需要体内结肠炎损伤后结肠上皮。完整上皮结构中细胞细胞接触的破坏是必要且足够用于L1CAM诱导，随着时间的流逝，表达随着上皮为再生。我们假设上皮崩解诱导L1CAM表达，这是侵袭，转移和治疗后癌细胞的生存和改革。这些机制将在肿瘤进展过程中诱导L1CAM依赖性（使用患者衍生的类器官模型）定义（1）转移性CRC以定义上皮连接下游L1CAM的转录调节解离，（2）使用一般工程的鼠标模型，尖端的器官衍生的原位直肠移植，在体内的原位肝和肺转移模型，以确定L1CAM在肿瘤起始，局部入侵，转移性定殖和维持。拟议的调查将描绘肿瘤传播诱导表型可塑性和出现的信号通路转移性性状，并将为抑制转移再生的L1CAM靶向药物铺平道路。这申请人Karuna Ganesh博士，纪念Sloan Kettering的胃肠道肿瘤学服务教练癌症中心（MSKCC）划定了一项为期5年的职业计划，以她的研究背景为基础医学肿瘤学的生物化学和临床培训。该项目将为Ganesh博士提供理想的培训在使用临床代表性的，最先进的患者衍生的类器官和小鼠模型时进行剖析转移的转录和表观遗传调节。 Ganesh博士将由JoanMassagué博士指导国际著名的转移专家，具有良好的培训成功记录成功的独立记录物理科学家。候选人的职业发展计划包括课程，研讨会，来自跨学科咨询委员会完成了杰出的基础科学家和医学肿瘤学家，以及 MSKCC杰出机构环境的研究经验，MSKCC是卓越的中心转化癌研究。成功完成研究项目将导致新方法治疗转移性癌症患者，并将为Ganesh博士过渡到某个位置的基础作为自己的实验室和R01资金的独立调查员。