Docking Protein p130Cas Regulates Acinar to Ductal Metaplasia During Pancreatic Adenocarcinoma Development and Pancreatitis

Gastroenterology. 2022 Apr;162(4):1242-1255.e11. doi: 10.1053/j.gastro.2021.12.242. Epub 2021 Dec 17.


Background & aims: Acinar to ductal metaplasia is the prerequisite for the initiation of Kras-driven pancreatic ductal adenocarcinoma (PDAC), and candidate genes regulating this process are emerging from genome-wide association 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: We found that high expression of p130Cas is frequently detected in 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 means of 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 acinar to ductal metaplasia and subsequent tumor initiation. This demonstrates an unexpected driving role of p130Cas downstream of Kras through PI3K/AKT, thus indicating a rational therapeutic strategy of targeting the PI3K pathway in tumors with high expression of p130Cas.

Keywords: ADM; Carcinogenesis; Kras; Metaplasia; PDAC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells / pathology
  • Adenocarcinoma* / pathology
  • Animals
  • Carcinogenesis
  • Carcinoma, Pancreatic Ductal* / pathology
  • Cell Transformation, Neoplastic / pathology
  • Crk-Associated Substrate Protein* / metabolism
  • Genome-Wide Association Study
  • Humans
  • Metaplasia / pathology
  • Mice
  • Pancreatic Neoplasms* / pathology
  • Pancreatitis / chemically induced
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins p21(ras) / metabolism


  • BCAR1 protein, human
  • Crk-Associated Substrate Protein
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins p21(ras)

Supplementary concepts

  • Pancreatic Carcinoma