Regulation and targeting of tumor cell states and plasticity in pancreatic cancer

项目摘要/摘要：转移性胰腺导管腺癌(PDAC)是一种侵袭性和致命性的肿瘤。 恶性疾病，几乎没有治疗选择。肿瘤转录状态与治疗密切相关 PDAC的反应和临床结果。然而，调节PDAC细胞状态的机制及其 其在肿瘤演变和治疗耐药中的作用尚不清楚。在这份提案中，我将调查 调节PDAC细胞状态规范的机制，将肿瘤细胞的可塑性表征为潜在的机制 治疗耐药性，并确定细胞状态特定的治疗脆弱性使用基因和 药理学方法。在目标1中，我将研究转化生长因子-β信号如何指定基础细胞状态 器官模型。在目标2中，我将研究转化生长因子-β介导的细胞可塑性是否会导致化疗耐药。 器官模型和连续收集的转移活检组织进行单细胞RNA测序分析。在《目标3》中， 我将在诱导采用以下两种方法之一的同源类有机物模型中进行化合物测试和CRISPR筛选 基础状态或经典状态，以确定特定状态的治疗脆弱性。综合起来，这些目标将确立 一个用于分析和建模PDAC演进的严格框架，并将推动我们的机制 了解转化生长因子-β等微环境因素如何调节PDAC细胞状态、可塑性和药物 从而为治疗开发开辟了新的途径。 我是一名内科肿瘤学家，专注于胃肠道癌症的临床研究，并具有 癌症生物学和生物医学工程。我正在申请K08奖项，长期目标是成为 以实验室为基础的独立研究人员，专注于胰腺癌和胆道癌的翻译研究。在.期间 我的K08培训，我将在达纳-法伯的威廉·哈恩博士的实验室进行指导性研究 癌症研究所(DFCI)。布莱恩·沃尔平博士将担任我研究翻译方面的联合导师 还将担任我的临床导师。我计划将90%的时间用于研究，10%的时间用于研究 在病人护理方面，最初作为住院肿瘤科主治医师，但最终过渡到门诊环境 在那里我会看到胃肠道癌症患者。我组织了一个杰出的顾问委员会 由DFCI、哈佛医学院、布罗德研究所和麻省理工学院的教职员工组成，帮助指导我的研究 和职业发展。除了哈恩博士和沃尔平博士，我的委员会成员-拉梅什博士 Shivdasani、Stuart Schreiber、Alex Shalek和Stephanie Dougan-是我的特定领域的科学专家 他们提出的研究，以及他们的见解，将被证明对成功完成这项提议是非常宝贵的。这个 DFCI和布罗德研究所的研究环境无与伦比，为以下方面提供了无数机会 科学进步和事业发展。K08奖以及我的导师和一个专注的 培训计划将使我能够实现成为一名独立的内科科学家的目标。

Project Summary/Abstract: Metastatic pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy with few therapeutic options. Tumor transcriptional states are strongly correlated with therapeutic responses and clinical outcomes in PDAC. However, the mechanisms that regulate PDAC cell states and their roles in tumor evolution and therapeutic resistance are not well understood. In this proposal, I will investigate mechanisms regulating PDAC cell state specification, characterize tumor cell plasticity as a potential mechanism of therapeutic resistance, and identify cell state-specific therapeutic vulnerabilities using genetic and pharmacologic approaches. In Aim 1, I will investigate how TGF-β signaling specifies the basal cell state in organoid models. In Aim 2, I will examine whether TGF-β-mediated cellular plasticity drives chemo-resistance in organoid models and serially collected metastatic biopsies analyzed with single-cell RNA-sequencing. In Aim 3, I will perform compound testing and CRISPR screening in isogenic organoid models induced to adopt either basal or classical states to identify state-specific therapeutic vulnerabilities. Together, these aims will establish a rigorous framework for the analysis and modeling of PDAC evolution and will advance our mechanistic understanding of how microenvironmental factors such as TGF-β regulate PDAC cell states, plasticity, and drug resistance, thereby uncovering new avenues for therapeutic development. I am a medical oncologist with a clinical focus in gastrointestinal cancers and a research background in cancer biology and biomedical engineering. I am applying for the K08 award with the long-term goal of becoming an independent laboratory-based investigator with a translational focus in pancreatic and biliary cancers. During my K08 training, I will perform mentored research in the laboratory of Dr. William Hahn at the Dana-Farber Cancer Institute (DFCI). Dr. Brian Wolpin will serve as a co-mentor for the translational aspects of my research and will also act as my clinical mentor. I plan to spend 90% of my time performing research and 10% of my time on patient care, initially as an inpatient oncology attending but eventually transitioning to the outpatient setting where I will see patients with gastrointestinal cancers. I have organized an outstanding advisory committee consisting of faculty from DFCI, Harvard Medical School, the Broad Institute, and MIT to help guide my research and career development. In addition to Drs. Hahn and Wolpin, my committee members - Drs. Ramesh Shivdasani, Stuart Schreiber, Alex Shalek, and Stephanie Dougan - are scientific experts in specific areas of my proposed research, and their insights will prove invaluable to the successful completion of this proposal. The research environments at DFCI and the Broad Institute are unparalleled and offer numerous opportunities for scientific advancement and career development. The K08 award along with the aid of my mentors and a focused training plan will enable me to achieve my goal of becoming an independent physician-scientist.