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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.

项目概要由于能够自我修复的耐药亚克隆的出现，转移性癌症总是会复发。更新、缓慢的细胞周期、肿瘤重新启动和治疗抵抗，称为转移干细胞（MetSC）。然而，人们对 MetSC 生存和再生的分子机制知之甚少。初步的该提案中描述的数据将细胞粘附分子细胞粘附分子 L1 (L1CAM) 识别为抑制转移复发的关键目标。采用新颖的源自患者的类器官治疗模型抗性结直肠癌 (CRC) 肝转移，患者肿瘤中的 L1CAM+ 细胞被证明选择性地离体再生类器官。 L1CAM 是体外类器官再生所必需的，而小鼠体内结肠炎损伤后的结肠上皮。完整上皮结构中细胞与细胞接触的破坏是 L1CAM 诱导是必要且充分的，随着上皮细胞的生长，表达会随着时间的推移而减少再生了。我们假设上皮不完整会诱导 L1CAM 表达，这是癌细胞在侵袭、转移和治疗后的存活和再生。的机制将使用源自患者的类器官模型定义 (1) 在肿瘤进展过程中诱导 L1CAM 依赖性转移性 CRC 的研究确定上皮连接下游 L1CAM 的转录调控解离和（2）使用基因工程小鼠模型，尖端的类器官衍生的原位直肠移植以及体内原位肝和肺转移模型以确定 L1CAM 在肿瘤发生、局部侵袭、转移定植和维持。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特征，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，纪念斯隆凯特林胃肠肿瘤服务讲师癌症中心 (MSKCC) 制定了一个基于她在以下领域的研究背景的 5 年职业计划：肿瘤内科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使用具有临床代表性、最先进的患者来源的类器官和小鼠模型来剖析转移的转录和表观遗传调控。 Ganesh 博士将接受 Joan Massagué 博士的指导，Joan Massagué 博士是一位国际知名转移专家，拥有成功独立培训的良好记录医师科学家。候选人的职业发展计划包括课程、研讨会、指导由杰出的基础科学家和医学肿瘤学家组成的跨学科咨询委员会，以及 MSKCC 卓越的机构环境中的研究经验转化癌症研究。该研究项目的成功完成将带来新的方法治疗转移性癌症患者，将为 Ganesh 博士的过渡奠定基础作为一名独立调查员，拥有自己的实验室和 R01 资助。