Oncofetal Proteins Drive Aggressive Disease in Basal Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer arising from the exocrine pancreas. Unlike most other solid tumors, incidence and mortality from PDAC continues to rise in the United States. PDAC is typically diagnosed after it has metastasized to other organs, and the only treatment option for advanced disease is combination chemotherapy. Targeted small molecule inhibitors and immunotherapies have encountered rapid resistance and are not yet clinically approved. Identifying disease subtypes and targeting therapies to these subtypes remains of crucial importance to improve outcomes.We have found that the chromatin-associated protein high mobility group AT-hook 2 (HMGA2) is differentially regulated in the most lethal subtypes of PDAC. In addition to predicting worse overall survival, high levels of HMGA2 in primary tumors also correlate with shorter time to disease recurrence and chemoresistance. In preclinical studies, HMGA2 expression is sufficient to drive aggressive disease in human and murine models of PDAC and leads to increased translation. This phenotype can be specifically targeted with inhibitors of protein synthesis. Finally, HMGA2 levels lead to altered cytokine secretion from tumor cells, fundamentally reshaping the tumor microenvironment and potentially defining key targets to rewire the profound immunosuppression seen in these tumors. Together, these studies define the oncofetal protein HMGA2 as a driver of aggressive disease in PDAC and elucidate the intracellular and extracellular mechanisms that lead to this lethal phenotype. We propose that levels of HMGA2 can be used clinically to define subsets of PDAC patients who will respond to targeted and immune modulating therapies.