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

转移性胰腺导管腺癌（PDAC）是一种侵袭性和致命性的肿瘤， 几乎没有治疗选择的恶性肿瘤。肿瘤的转录状态与治疗效果密切相关。 PDAC中的反应和临床结局。然而，调节PDAC细胞状态的机制及其 在肿瘤演变和治疗抗性中的作用还不清楚。在这份提案中，我将调查 调节PDAC细胞状态特化的机制，将肿瘤细胞可塑性表征为潜在机制 的治疗耐药性，并确定细胞状态特异性的治疗漏洞，使用遗传和 药理学方法。在目标1中，我将研究TGF-β信号如何指定基底细胞状态， 类器官模型在目标2中，我将研究TGF-β介导的细胞可塑性是否驱动了化疗耐药。 类器官模型和连续收集的转移性活检用单细胞RNA测序分析。在目标3中， 我将在诱导采用以下任一种方法的等基因类器官模型中进行化合物测试和CRISPR筛选： 基础或经典状态，以识别状态特异性治疗弱点。这些目标将共同建立 一个严格的框架，分析和建模的PDAC演变，并将推进我们的机制 了解微环境因素如TGF-β如何调节PDAC细胞状态、可塑性和药物 耐药性，从而发现新的治疗发展途径。 我是一名医学肿瘤学家，临床重点是胃肠道癌症，并有以下研究背景： 癌症生物学和生物医学工程。我申请K08奖的长期目标是成为 一个独立的实验室为基础的调查与翻译重点在胰腺癌和胆管癌。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研究 癌症研究所（DFCI）。布莱恩·沃尔平博士将担任我的研究转化方面的共同导师 同时也是我的临床导师我计划用90%的时间做研究， 病人护理，最初作为住院肿瘤科主治，但最终过渡到门诊设置 在那里我会看到患有胃肠癌的病人。我组织了一个出色的咨询委员会 由DFCI、哈佛医学院、布罗德研究所和麻省理工学院的教师组成，帮助指导我的研究 和职业发展。除了哈恩和沃尔平博士，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。 建议的研究，他们的见解将证明是非常宝贵的，成功完成这一建议。的 DFCI和布罗德研究所的研究环境是无与伦比的，为以下人员提供了许多机会： 科技进步和事业发展。K08奖沿着与我的导师和一个专注的援助 培训计划将使我能够实现我的目标，成为一个独立的物理学家，科学家。

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.