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Docking protein p130Cas regulates acinar to ductal metaplasia during pancreatic adenocarcinoma development and pancreatitis.

BACKGROUND AND AIMS
Acinar to Ductal Metaplasia (ADM) is the prerequisite for the initiation of Kras-driven pancreatic adenocarcinoma (PDAC) and candidate genes regulating this process are emerging from GWAS studies. The adaptor protein p130Cas emerged as a potential PDAC susceptibility gene and a Kras-synthetic lethal interactor in pancreatic cell lines, however its role in PDAC development has remained largely unknown.


METHODS
Human PDAC samples and murine KrasG12D-dependent pancreatic cancer models of increasing aggressiveness were used. p130Cas was conditionally ablated in pancreatic cancer models to investigate its role during Kras-induced tumorigenesis RESULTS: Here, we show that high expression of p130Cas is frequently detected in Pancreatic ductal adenocarcinoma (PDAC) and correlates with higher histologic grade and poor prognosis. In a model of Kras-driven PDAC, loss of p130Cas inhibits tumor development and potently extends median survival. Deletion of p130Cas suppresses acinar-derived tumorigenesis and progression by repressing PI3K-AKT signaling, even in the presence of a worsening condition like pancreatitis.


CONCLUSIONS
Our observations finally demonstrated that p130Cas acts downstream of Kras to boost the PI3K activity required for ADM and subsequent tumor initiation. This demonstrates an unexpected driving role of p130Cas downstream of Kras through the PI3K/AKT, thus indicating a rational therapeutic strategy of targeting the PI3K pathway in tumors with high expression of p130Cas.