RRC ID 71804
Author Nagao M, Fukuda A, Omatsu M, Namikawa M, Sono M, Fukunaga Y, Masuda T, Araki O, Yoshikawa T, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Taketo MM, Ferrer J, Tsuruyama T, Nakanuma Y, Taura K, Uemoto S, Seno H.
Title Concurrent Activation of Kras and Canonical Wnt Signaling Induces Premalignant Lesions That Progress to Extrahepatic Biliary Cancer in Mice.
Journal Cancer Res
Abstract Biliary cancer has long been known to carry a poor prognosis, yet the molecular pathogenesis of carcinoma of the extrahepatic biliary system and its precursor lesions remains elusive. Here we investigated the role of Kras and canonical Wnt pathways in the tumorigenesis of the extrahepatic bile duct (EHBD) and gall bladder (GB). In mice, concurrent activation of Kras and Wnt pathways induced biliary neoplasms that resembled human intracholecystic papillary-tubular neoplasm (ICPN) and biliary intraepithelial neoplasia (BilIN), putative precursors to invasive biliary cancer. At a low frequency, these lesions progressed to adenocarcinoma in a xenograft model, establishing them as precancerous lesions. Global gene expression analysis revealed increased expression of genes associated with c-Myc and TGFβ pathways in mutant biliary spheroids. Silencing or pharmacologic inhibition of c-Myc suppressed proliferation of mutant biliary spheroids, whereas silencing of Smad4/Tgfbr2 or pharmacologic inhibition of TGFβ signaling increased proliferation of mutant biliary spheroids and cancer formation in vivo. Human ICPNs displayed activated Kras and Wnt signals and c-Myc and TGFβ pathways. Thus, these data provide direct evidence that concurrent activation of the Kras and canonical Wnt pathways results in formation of ICPN and BilIN, which could develop into biliary cancer.
SIGNIFICANCE:This work shows how dysregulation of canonical cell growth pathways drives precursors to biliary cancers and identifies several molecular vulnerabilities as potential therapeutic targets in these precursors to prevent oncogenic progression.
Volume 82(9)
Pages 1803-1817
Published 2022-5-3
DOI 10.1158/0008-5472.CAN-21-2176
PII 681971
PMID 35247892
MeSH Animals Bile Duct Neoplasms* / genetics Bile Duct Neoplasms* / pathology Bile Pigments / metabolism Biliary Tract Neoplasms* / genetics Carcinoma in Situ* / pathology Humans Mice Precancerous Conditions* / pathology Proto-Oncogene Proteins p21(ras) / genetics Proto-Oncogene Proteins p21(ras) / metabolism Transforming Growth Factor beta / metabolism Wnt Signaling Pathway / genetics
IF 9.727
DNA material pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)