Pancreatic cancer has notoriously ineffective treatment options and will take the lives of over 50,000 individuals in the U.S. this year. We have a vibrant team applying innovative bench and computational approaches to pioneer a cancer “interception” strategy: a way to restrain or revert pancreas precursor lesions before they have a chance to become cancer.
Current Projects:
Epigenetic determinants of pancreas cell identity:
The identity of acinar cells, the cell of origin of pancreatic cancer, is maintained by a gene regulatory network of transcription factors and epigenetic states. How are these regulators of normal cell identity disrupted by stressors that promote cancer (inflammation, obesity, and an oncogenic Kras mutation)? And, can we target these regulators to stabilize normal cell identity for cancer interception? Interested students will have access to a complement of mouse models, human pancreas cultures, new transcriptomic and epigenomic pipelines developed in the lab, and functional tools to help answer these questions.
“Amnesia” of prior inflammatory stress:
Cells that recover from inflammation are thought to harbor epigenetic scars that distinguish them from naïve cells. These scars may explain why pancreatitis is a risk factor for pancreatic cancer. During pancreatitis, acinar cells transiently undergo metaplasia but then completely recover histologically. Though they appear normal, these recovered acinar cells have durable epigenetic marks of metaplasia that may facilitate cancer initiation. Interested students can (i) define these epigenetic marks and (ii) determine whether we can pharmacologically reverse these epigenetic marks to achieve “amnesia” of pancreatitis as an interception strategy for cancer.
Reprogramming the immune microenvironment in pancreas cancer formation:
Pancreatic cancer is refractory to immunotherapy due to active evasion mechanisms. In this project, students will study how stressors that promote pancreatic cancer (including obesity, inflammation, and an oncogenic Kras mutation) reprogram the pancreas microenvironment to actively suppress immune surveillance.
CRISPR somatic genome engineering in mouse pancreas:
Single cell transcriptomic and epigenomic studies identify candidate pathways that regulate pancreas biology and disease. However, tools to functionally validate these pathways in the pancreas are limited. In this project, students will help establish in vivo CRISPR-mediated genome engineering in the mouse pancreas that will be critical to validate strategies for pancreatic cancer interception and treatment.
Understanding metabolic dysfunction in the pancreas:
The pancreas is composed of histologically distinct exocrine and endocrine compartments. Individuals diagnosed with pancreatic cancer often initially present with metabolic abnormalities including new-onset diabetes and severe weight loss, suggesting that an incipient cancer dysregulates adjacent endocrine pancreas cells. In this project, students will harness single cell and spatial transcriptomic tools to understand mechanisms of crosstalk between the exocrine and endocrine pancreas in the context of obesity, pancreatitis, and cancer.
Contact: snissim [at] bwh.harvard.edu
Lab Location: Longwood