# Nilay Senthi Assistant Professor of Medicine ![Sethi](/sites/g/files/omnuum5321/files/styles/hwp_4_5__480x600/public/2024-10/Untitled%206_1.jpg?itok=KmIrCVmx) smartphone [617-632-3693](tel:617-632-3693) email [nilay\_sethi@dfci.harvard.edu](mailto:nilay_sethi@dfci.harvard.edu) Dana Farber Cancer Institute 450 Brookline Avenue, D740C Boston, MA 02215 The overall goal of the Sethi lab is to combine clinical observations and patient-derived data with rigorous basic science investigation to yield opportunities for impactful translational advances. Our passion for investigative research is fundamentally dependent upon its power to generate a deeper understanding of human disease and ultimately improve patient care. We are particularly committed to defining the fundamental mechanisms underlying gastrointestinal cancers with the hope that such insight will translate into new prevention and treatment methods. Projects in the lab generally start by thinking deeply about the clinical circumstances that encase the diagnosis, management, and treatment of gastrointestinal cancers. With this holistic view in mind, we aim to identify unmet needs and clear gaps in translation, which directly inform the design of molecular studies involving patient samples (Cancer Genomics). The molecular studies describe key features of human disease and help generate new, testable hypotheses. Patient-derived data help guide the development of innovative models that are designed to recapitulate human disease and utilized to rigorously test emergent hypotheses (Disease Models). The combination of patient-derived molecular data and faithful models help elucidate crucial disease mechanisms that promote cancer progression. The insight gained directly informs new screening platforms to uncover molecular dependencies and hopefully lead to drug discovery (Therapeutic Vulnerabilities). Our lab applies this investigative philosophy to two main areas of gastrointestinal cancer research. Gastric and esophageal cancers: We are devoted to better understanding cancers of the stomach and lower esophagus. Using model systems that integrate disease risk factors with early genetic mistakes, we aim to study the premalignant state, hoping to learn how somatic mutations engage environmental exposures during the initiation of these cancers. These models have yielded new insight into disease progression, revealing therapeutic vulnerabilities that are actively being investigated in preclinical systems. By leveraging data from patients, mouse models, and cell culture studies, we are motivated to provide an integrated understanding of early events in gastrointestinal cancers with the ultimate hope that the knowledge gained will inspire new avenues for cancer prevention and treatment. Colorectal cancer: Our lab is invested in a deeper understanding of colorectal cancer, which remains the second leading cause of cancer-mortality worldwide and responsible for an alarming trend of increasing incidence in younger patients. The intestine is a is the most rapidly renewing tissue in our body; the gut lining is replenished every 2 to 5 days. Maintaining the intestinal lining therefore requires stem cells to constantly give rise to mature cells to perform their specialized function before dying. Disruption of this natural maturation is a hallmark of colorectal cancer. Our lab is focused on defining the molecular components that block proper differentiation in cancer cells. We use genetically engineered and carcinogen-induced mouse models as well as derivative organoids to study the molecular mediators that impair differentiation. We apply bulk and single cell epigenomic and transcriptomic profiling to help define disease mechanisms and identify new regulators. Based on some this knowledge, we have designed a unique discovery platform to help us screen chemical compound libraries with the goal of identifying specific agents that overcome this block in maturation. We strongly believe the next generation of therapeutics will restore proper maturation in colon cancer cells, reprogramming them to live out their natural life cycle. - ## Program Affiliation [Leder Human Biology](/bbs-faculty/leder-human-biology) - ## People [Faculty](/people/faculty) - ## Location [Dana Farber Cancer Institute](/location/dana-farber-cancer-institute)