Abstract IA25: Metastatic programs in pancreas cancer
Authors: Hingorani Sunil R. 
Published: May 2016

The unusually high metastatic proclivity of pancreas cancer is life-limiting for a majority of patients including those treated at early stages. A minority of patients nevertheless presents with and succumbs to locally destructive disease. These distinct disease presentations and predilections for distant spread versus local growth of the primary tumor also suggest that the appropriate selection and application of systemic versus local therapies might increase their efficacy and prolong patient survival. We have undertaken a systematic effort to dissect the pathophysiologic mechanisms underlying the extreme lethality of pancreatic ductal adenocarcinoma (PDA) primarily through the generation and study of genetically engineered mouse models (GEMMs) of the disease. These models faithfully recapitulate the clinical syndrome, histopathology, molecular features and response and resistance to treatments seen in the human disease. We previously showed that point-mutant forms of Trp53 cooperate with oncogenic KrasG12D to promote widely metastatic disease in a GEMM of PDA. These and other studies have revealed that distinct combinations of tumor suppressor gene mutations can alter the pace, phenotype and prognosis of the resultant invasive disease initiated by oncogenic Kras. We have recently developed model systems that manifest the two ends of the disease phenotype described above and identified the Runx3/RUNX3 transcription factor as a master regulator of a metastatic program that dictates the balance between cell division and dissemination. Acting in concert with point-mutant Trp53 and distinct gene dosages of Dpc4/Smad4, Runx3 suppresses local growth at the expense of distant spread. Thus, Runx3 can serve as both tumor suppressor and promoter depending on the specific disease behavior in question. Runx3 promotes the invasive and migratory capabilities of PDA cells and activates a secretory program of proteins to construct a favorable microenvironment for newly migrant cells in foreign tissues such as the liver and lungs. Perhaps not surprisingly for such a potentially important behavioral switch, Runx3 levels are regulated by several inputs operating at both the transcriptional and post-translational levels. We observed a biphasic dependency of Runx3 levels on Dpc4 gene dosage in PDA which also correlates with metastatic potential. Integrating these findings, we propose a presumptive rule set to predict and explain three potential disease presentations in patients: 1) metastatic disease predominant; 2) local growth predominant; and 3) tumors with both rapid primary tumor growth and significant disseminated disease in an extraordinarily lethal combination. These three definable states also immediately suggest whether local (surgery, radiation) vs. systemic (chemotherapy) interventions should be implemented or prioritized. Thus, in addition to providing additional therapeutic targets to impede or inhibit PDA cells from establishing a clinically meaningful metastatic disease burden, this understanding has the potential to more rationally inform the specific application and timing of distinct therapeutic modalities already at hand to optimize survival.

Citation Format: Sunil R. Hingorani. Metastatic programs in pancreas cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA25.