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

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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.