RT Journal Article
SR Electronic
T1 Loss of <em>Jag1</em> cooperates with oncogenic <em>Kras</em> to induce pancreatic cystic neoplasms
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900503
DO 10.26508/lsa.201900503
VO 4
IS 2
A1 Wen-Cheng Chung
A1 Lavanya Challagundla
A1 Yunyun Zhou
A1 Min Li
A1 Azeddine Atfi
A1 Keli Xu
YR 2021
UL https://www.life-science-alliance.org/content/4/2/e201900503.abstract
AB 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.