Simultaneous activation of Kras–Akt and Notch pathways induces extrahepatic biliary cancer via the mTORC1 pathway

• DOI: 10.1002/path.6139
• Publication Date: 2023-06-13T12:28:51Z
• Authors: Mio Namikawa; Akihisa Fukuda; Kenta Mizukoshi; Kosuke Iwane; Munenori Kawai; Go Yamakawa; Mayuki Omatsu; Makoto Sono; Tomonori Masuda; Osamu Araki; Munemasa Nagao; Takaaki Yoshikawa; Satoshi Ogawa; Yukiko Hiramatsu; Yu Muta; Motoyuki Tsuda; Takahisa Maruno; Yuki Nakanishi; Tatsuaki Tsuruyama; Kojiro Taura; Etsuro Hatano; Hiroshi Seno
• Keywords: Cholangiocarcinoma; Mice; Phosphatidylinositol 3-Kinases; Biliary Tract Neoplasms; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Humans; Animals; Mechanistic Target of Rapamycin Complex 1; Proto-Oncogene Proteins c-akt; Carcinoma in Situ; 3. Good health

Biliary tract cancer (BTC) has poor prognosis. The Notch receptor is aberrantly expressed in extrahepatic cholangiocarcinoma (eCCA). However, the role of signaling initiation and progression eCCA gallbladder (GB) remains unknown. Therefore, we investigated functional during tumorigenesis bile duct (EHBD) GB. Activation oncogenic Kras resulted development biliary intraepithelial neoplasia (BilINs) EHBD GB, which were premalignant lesions that progressed to adenocarcinoma mice. expression genes involved mTORC1 pathway was increased spheroids from Hnf1b-CreERT2; KrasLSL-G12D ; Rosa26LSL-NotchIC mice inhibition suppressed spheroid growth. Additionally, simultaneous activation PI3K-AKT pathways GB induced Consistent with this, observed a significant correlation between activated NOTCH1 phosphorylated Ribosomal Protein S6 (p-S6) human eCCA. Furthermore, growth Notch-activated cells vitro vivo. Mechanistically, Kras/Notch-Myc axis through TSC2 phosphorylation mutant spheroids. These data indicate could be an effective treatment strategy for © 2023 Pathological Society Great Britain Ireland.