Boston University Chobanian & Avedisian School of Medicine
Early-onset chronic pancreatitis alters the trajectory of PanIN development associated with oncogenic KRAS
Overview
Aim: Cancer Biology
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a five-year survival rate under 13% and limited therapeutic options. Although nearly all PDAC tumors carry mutations in the KRAS gene, these mutations alone are insufficient to drive cancer. Chronic inflammation of the pancreas, particularly in hereditary pancreatitis commonly caused by mutation in the PRSS1 gene, is a well-established risk factor, yet how it shapes the earliest precancerous changes is not fully understood. We have developed a new model that combines oncogenic KRAS activation with a digestive enzyme trypsinogen mutation that causes severe, early onset pancreatitis. Unexpectedly, these mice formed precancerous PanIN lesions unusually early, but the lesions regressed within weeks, suggesting that under certain inflammatory conditions, early cancerous changes can be reversed.
Our research will investigate the cellular, molecular, and immune mechanisms that determine whether PanIN lesions persist, regress, or never develop. We will compare severe and mild hereditary pancreatitis models to assess how the timing and intensity of inflammation influence pancreatic cell fate. By integrating histological, transcriptional, and immune profiling approaches, we aim to uncover natural protective mechanisms that halt early tumor development. These insights could inform new strategies to prevent PDAC in individuals at high risk due to chronic pancreatitis or other inflammatory conditions.
