Defining the role of GNAS in gastrointestinal metastasis

项目摘要/摘要 腹膜腔胃肠道(GI)转移患者的发病率很高， 化疗耐药，总体存活率下降。分子机制及表型特征 促进腹膜转移的机制目前知之甚少，尽管粘蛋白表达的肿瘤表现为 极易发生腹膜扩散。初步分析确定，在泛癌症患者队列中 粘液性胃肠道肿瘤高度富含GNAS中的一种特定突变，该突变导致致病获得- 在编码的G蛋白α亚单位(GNAS)中起作用。GNAS突变与胰腺和胰腺癌相关 小细胞肺癌的发生，但GNAS动员促进转移的致病机制 是未知的。初步数据显示，GNAS突变的胃肠道癌症患者表现出增加 腹膜转移的负担，对一线化疗的反应降低，总体存活率低。 对来自独立患者肿瘤组的肿瘤DNA和RNA的分析表明，突变的GNAS可能 在一个独特的基因调控网络中工作，激活PI3K和MAPK信号。圆周率和 合作者建立了GNAS突变的患者衍生器官(PDO)和腹膜转移 小鼠模型评估GNAS是控制信号转导的关键分子驱动因素的假设 参与转移性腹膜种植和生长的途径。 为了验证这一假设，这项研究将(1)定义GNAS诱导的基因调控网络和 促进腹膜转移患者肿瘤进展的表型特征和CRISPR-Cas9基因- 编辑的PDO和(2)确定GNAS调节对肿瘤转移分布和致病性的影响 体内采用异种移植瘤转移模型。调查将把多经济分析与PDO相结合 提高对转移的基本理解并验证GNAS信号的实验验证 作为与治疗相关的靶点。申请者Michael Foote博士是GI的一名正在崛起的助理 纪念斯隆·凯特琳癌症中心(MSKCC)的肿瘤学服务。Foote博士制定了一个五年计划 将他在靶向药物开发和计算生物信息学方面的背景与新的专业知识相结合 在实验建模和分子生物学方面。Foote博士将接受辅助性建议的指导 由路易斯·迪亚兹博士领导的委员会，他是一位有很强培训背景的国际基因组学专家 成功的独立内科科学家。Foote博士的发展计划包括支持性研讨会和 由分子生物学、细胞信号和生物信息学专家组成的咨询委员会在 MSKCC，世界著名的翻译卓越中心。项目目标的完成将促进新的 转移性胃肠道癌的治疗方法和Foote博士发展成为独立的 胃肠道转移方面的内科科学家和专家领袖。

PROJECT SUMMARY/ABSTRACT Patients with gastrointestinal (GI) metastases in the peritoneal cavity suffer high morbidity, chemotherapy resistance, and decreased overall survival. The molecular mechanism and phenotypic features that facilitate peritoneal metastasis are poorly understood, although mucin-expressing tumors exhibit especially high predilection for peritoneal spread. Preliminary analyses determined in a pan-cancer patient cohort that mucinous GI tumors are highly enriched in a specific mutation in GNAS that leads to pathogenic gain-of- function in the encoded G protein alpha subunit (GNAS). GNAS mutations are associated with pancreatic and small cell lung tumor development, yet the pathogenic mechanism mobilized by GNAS to facilitate metastasis is unknown. Preliminary data demonstrates that patients with GNAS-mutated GI cancers exhibit increased burden of peritoneal metastases, decreased response to first-line chemotherapy, and poor overall survival. Analysis of tumor DNA and RNA from independent groups of patient tumors shows that mutated GNAS may operate within a distinct gene-regulatory network that activates PI3K and MAPK signaling. The PI and collaborators established GNAS-mutated, patient-derived-organoids (PDOs) and a peritoneal metastasis mouse model to evaluate the hypothesis that GNAS is a key molecular driver that governs the signaling pathway involved in metastatic peritoneal seeding and growth. To test this hypothesis, the study will (1) define the GNAS-induced gene regulatory networks and phenotypic features that facilitate tumor progression in patient peritoneal metastasis and CRISPR-Cas9 gene- edited PDOs and (2) determine the impact of GNAS modulation on metastasis distribution and pathogenicity in vivo using xenograft metastatic models. Investigations will integrate multi-omic analyses with PDO experimental validation to improve the fundamental understanding of metastasis and validate GNAS signaling as a therapeutically-relevant target. The applicant, Dr. Michael Foote, is a rising Assistant Attending in the GI Oncology Service at Memorial Sloan Kettering Cancer Center (MSKCC). Dr. Foote has defined a 5-year plan to integrate his background in targeted drug development and computational bioinformatics with new expertise in experimental modeling and molecular biology. Dr. Foote will be mentored by a complementary advisory committee led by Dr. Luis Diaz, an international expert in genomics with a strong background in training successful independent physician scientists. Dr. Foote’s development plan includes supportive workshops and mentoring from an advisory committee of experts in molecular biology, cell signaling, and bioinformatics at MSKCC, a world-renowned translational center of excellence. Completion of the project goals will facilitate new therapeutic approaches for treating metastatic GI cancer and Dr. Foote’s development into an independent physician scientist and expert leader in GI metastasis.