Abstract 1573: Paradoxical roles of peritumoral myofibroblasts in intrahepatic cholangiocarcinoma growth and metastasis

Abstract

Abstract Background and Rationale: Intrahepatic cholangiocarcinoma (iCCA) is an aggressive type of primary liver cancer characterized by its highly desmoplastic stroma. Compared to the ample knowledge on the protumorigenic functions of iCCA intratumoral myofibroblasts (iMFs), little is known about the activation status of MFs in the tumor-surrounding liver (peritumoral myofibroblasts, pMFs) and their potential role in iCCA development. Results: We examined MF activation in both patient iCCA tumors and an iCCA orthotopic allograft mouse model. We found there was a significant, tumor-induced activation and accumulation of pMFs at the tumor border. Using an in vitro spheroid coculture system, we confirmed that iCCA-liver interaction induced rapid pMF activation at their interface. We found that MFs mixed within tumor spheroids as iMFs had a pro-proliferative effect on iCCA tumor cells similar to the previous reports. However, when the same MFs were seeded around iCCA spheroids as pMFs, they exerted a strong suppressive effect on tumor cells growth. Interestingly, prolonged iCCA-pMF coculture elicited marked tumor cell invasion and dissemination which did not occur in iCCA-iMF coculture. We found vascular cell adhesion protein 1 (Vcam1), a glycoprotein that has been implicated in solid tumor metastasis, was part of the dynamic regulation of tumor cell behaviors by iCCA-pMF interaction. Vcam1 was upregulated in the tumor cells at the early, growth-suppressing phase of iCCA-pMF interaction both in vitro and in vivo, and was then downregulated in tumor cells when they started to disseminate. Systemic blocking of Vcam1 activity in iCCA allograft mouse models using a Vcam1 neutralizing antibody slowed the primary tumor growth but promoted tumor cell dissemination. Conclusion: Our data suggest that pMFs are beyond simple pro- or anti-tumorigenic in iCCA development. iCCA development induces rapid activation and accumulation of pMFs at the tumor border which suppress tumor growth at early stage but eventually elicit tumor cell dissemination at late stage. Citation Format: Cheng Tian, Liyuan Li, Yizhen Li, Wentao Yang, Li Fan, Anthony Brown, Michelle Morrison, Jun J. Yang, Evan S. Glazer, Liqin Zhu. Paradoxical roles of peritumoral myofibroblasts in intrahepatic cholangiocarcinoma growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1573.