Loss of Jag1 cooperates with oncogenic Kras to induce pancreatic cystic neoplasms

Abstract

Notch signaling exerts both oncogenic and tumor-suppressive functions in the pancreas. In this study, deletion of Jag1 in conjunction with oncogenic KrasG12D expression in the mouse pancreas induced rapid development of acinar-to-ductal metaplasia and early stage pancreatic intraepithelial neoplasm; however, culminating in cystic neoplasms rather than ductal adenocarcinoma. Most cystic lesions in these mice were reminiscent of serous cystic neoplasm, and the rest resembled intraductal papillary mucinous neoplasm. Jag1 expression was lost or decreased in cystic lesions but retained in adenocarcinoma in these mice, so was the expression of Sox9. In pancreatic cancer patients, JAG1 expression is higher in cancerous tissue, and high JAG1 is associated with poor overall survival. Expression of SOX9 is correlated with JAG1, and high SOX9 is also associated with poor survival. Mechanistically, Jag1 regulates expression of Lkb1, a tumor suppressor involved in the development of pancreatic cystic neoplasm. Collectively, Jag1 can act as a tumor suppressor in the pancreas by delaying precursor lesions, whereas loss of Jag1 promoted a phenotypic switch from malignant carcinoma to benign cystic lesions.

External validation of genetically predicted protein biomarkers for pancreatic cancer risk using aptamer‐based plasma levels: A prospective analysis in the Atherosclerosis Risk in Communities Study

“…In addition to LIFsR, some of the other proteins that were statistically significantly or suggestively associated have been investigated in relation to pancreatic neoplasia in the context of early detection, diagnosis and prognosis 12,23‐27 . More research is needed to understand the potential biological consequences of the associations between the other 10 proteins and the risk of the development of pancreatic cancer.…”

“…Within the context of what is known about LIFsR and given the mediation findings from Zhu et al, our findings suggest a possible role for LIFsR in pancreatic cancer development, and thus risk. Nevertheless, we cannot rule out that LIFsR is marking later moments in the long preclinical phase of pancreatic cancer.In addition to LIFsR, some of the other proteins that were statistically significantly or suggestively associated have been investigated in relation to pancreatic neoplasia in the context of early detection, diagnosis and prognosis 12,[23][24][25][26][27]. More research is needed to understand the potential biological consequences of the associations between the other 10 proteins and the risk of the development of pancreatic cancer.…”