Srivatsan Raghavan

The Raghavan Lab at Dana-Farber Cancer Institute and Harvard Medical School is a basic and translational oncology lab focused on understanding mechanisms of cell state regulation in cancer, evaluating how cell state plasticity influences therapeutic response and tumor evolution, and applying these insights toward the discovery of new therapeutic approaches for patients with pancreatic and biliary cancers. Our multi-disciplinary research team uses a variety of innovative experimental and computational approaches including DNA and single-cell RNA sequencing of clinical samples, patient-derived organoid modeling, and functional genomic and pharmacologic screens to address several key areas, including:

Understanding how cell states and plasticity regulate therapeutic responses. Our work using single-cell RNA sequencing to analyze transcriptional phenotypes in metastatic pancreatic cancer clinical specimens and matched patient-derived organoids demonstrated that both genomic and microenvironmental factors such as TGF-β can regulate tumor cell state, and that cell state plasticity can dramatically alter drug sensitivity and contribute to therapeutic resistance. We are now dissecting the mechanisms by which different genomic alterations and signals from the tumor microenvironment influence cancer cell state, with the goal of identifying downstream signaling pathways that may be targetable. In addition, we seek to understand how these genomic and microenvironmental parameters coordinate to drive therapy resistance and tumor evolution over a patient’s clinical course.

Applying functional approaches for new target discovery. We have established robust methods to perform pharmacologic and genomic screens in cancer cell lines and organoid models. These approaches have led to the identification of compounds that inhibit a novel sulfur metabolism pathway and exhibit therapeutic effects in pre-clinical pancreatic cancer models. We are applying these approaches to identify context- and cell state-specific targets that may enable therapeutic combinations that limit drug resistance.

We actively collaborate with clinical, laboratory, and computational colleagues within the Hale Family Center for Pancreatic Cancer Research and more broadly at Dana-Farber Cancer Institute, Harvard Medical School, MIT, and the Broad Institute on basic and translational research projects with the shared goal of improving outcomes for patients with gastrointestinal cancers.