Concurrent activation of Kras and canonical Wnt signaling induces premalignant lesions that progress to extrahepatic biliary cancer in mice
Concurrent activation of Kras and canonical Wnt signaling induces premalignant lesions that progress to extrahepatic biliary cancer in mice
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Kras 和经典 Wnt 信号传导的同时激活可诱导小鼠癌前病变进展为肝外胆管癌
DOI：
10.1158/0008-5472.can-21-2176
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Seno H.
中科院分区：
文献类型：
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作者：
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.
胆道癌的预后一直被认为是很差的，但肝外胆道系统癌及其前病变的分子发病机制仍然是难以捉摸的。在这里，我们研究了Kras和经典Wnt通路在肝外胆管（EHBD）和胆囊（GB）肿瘤发生中的作用。在小鼠中，Kras和Wnt通路的同时激活诱导了类似于人胆囊内乳头状小管肿瘤（IPN）和胆管上皮内瘤变（BilIN）的胆管肿瘤，这些肿瘤被认为是浸润性胆管癌的前体。在低频率下，这些病变在异种移植模型中进展为腺癌，将其确立为癌前病变。整体基因表达分析显示，在突变的胆管球状体中，与c-Myc和TGFβ通路相关的基因表达增加。c-Myc的沉默或药物抑制抑制突变型胆管球体的增殖，而Smad 4/Tgfbr 2的沉默或TGFβ信号的药物抑制增加了体内突变型胆管球体的增殖和癌症的形成。人ICPNs显示激活的Kras和Wnt信号以及c-Myc和TGFβ通路。因此，这些数据提供了直接的证据表明，同时激活的Kras和经典Wnt途径的结果形成的ICPN和BilIN，这可能发展成biliary cancer.SignificanceThis工作显示如何失调的经典细胞生长途径驱动器的前体胆管癌，并确定了几个分子的脆弱性作为潜在的治疗目标，在这些前体，以防止致癌进展。
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 formationin 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.SignificanceThis 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.