The Hingorani laboratory investigates the molecular and cellular mechanisms that drive the pathogenesis of pancreatic ductal adenocarcinoma (PDA) or, more commonly, pancreas cancer. The inability to detect the disease early together with multiple mechanisms of chemical and radiotherapeutic resistance contribute to the extreme lethality of PDA. Our goal is to identify the most compelling strategies to translate to the clinic in order to cure this disease.
We have undertaken a systematic effort to deconstruct the cell autonomous and non-cell autonomous factors that cooperate to produce this unusually aggressive and lethal disease. To this end, we have helped to develop a number of genetically engineered, highly faithful animal models of preinvasive, invasive and metastatic PDA through the targeted endogenous expression of mutations in a key oncogene and select tumor suppressor genes. These models faithfully recapitulate the clinical syndrome, pathophysiology and molecular features of the distinct histopathologic routes to human pancreas cancer, including manifesting the unique stromal and immune responses that constitute the characteristic “desmoplastic reaction.” These models also serve as the primary platforms for our Murine Clinical Trials Program (“Mouse Hospital”) designed to accelerate the translation of early detection, diagnostic and treatment strategies to the clinic. As recent examples, our insights into combined stromal and epithelial cell targeting form the basis for international, randomized clinical trials currently underway. We have also characterized unusual physicomechanical properties of this cancer, with respect to an abundant interstitial gel-fluid phase, as well as identified a concerted transcriptional program that drives metastasis.