Investigating L1CAM-dependent stem cell regeneration in metastasis

项目摘要 转移性癌症总是复发，这是由于耐药亚克隆的出现，这些亚克隆能够自我调节， 更新、缓慢的细胞周期、肿瘤再启动和治疗抗性，称为转移干细胞（MetSC）。 然而，MetSCs用于存活和再生的分子机制知之甚少。初步 本提案中描述的数据将细胞粘附分子细胞粘附分子L1（L1CAM）鉴定为 抑制转移复发的关键靶点。采用新型患者源性类器官治疗模型- 对于耐药结肠直肠癌（CRC）肝转移，患者肿瘤中的L1CAM+细胞显示出选择性地 离体再生类器官。L1CAM是体外类器官再生所必需的， 体内结肠炎损伤后的结肠上皮。破坏完整上皮结构中的细胞-细胞接触， 对于L1CAM诱导是必要的和足够的，随着时间的推移表达减少，因为上皮细胞是 重生了我们假设上皮不完整诱导L1CAM表达，这是细胞增殖所必需的。 癌细胞在侵袭、转移和治疗后的存活和再生长。的机制 在肿瘤进展期间诱导L1CAM依赖性将被定义（1）使用患者来源的类器官模型 以确定上皮连接下游L1CAM的转录调节 解离和（2）使用基因工程小鼠模型，尖端类器官来源的原位 直肠移植和原位肝和肺转移模型，以确定L1CAM在 肿瘤起始、局部侵袭、转移定植和维持。拟议的调查将 描绘肿瘤播散诱导表型可塑性和出现的信号通路 的转移特性，并将铺平道路L1CAM靶向药物，抑制转移再生。的 申请人，Karuna Ganesh博士，纪念斯隆凯特琳胃肠肿瘤服务讲师 癌症中心（MSKCC），已经描绘了一个5年的职业规划，建立在她的研究背景， 生物化学和临床医学肿瘤学培训。该项目将为Ganesh博士提供理想的培训 在使用临床代表性的、最先进的患者源性类器官和小鼠模型来解剖 转移的转录和表观遗传调节。Ganesh博士将由Joan Massagué博士指导， 国际知名的转移专家，拥有成功的独立培训记录 医学科学家候选人的职业发展计划包括课程，研讨会， 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 在MSKCC的优秀制度环境的研究经验，卓越的中心， 转化性癌症研究研究项目的成功完成将导致新的方法， 治疗转移性癌症患者，并将为Ganesh博士过渡到一个职位提供基础。 作为一个独立的调查员，她有自己的实验室和R01基金。

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.