TY - JOUR T1 - Spatiotemporal Dynamics of Vcam1 Regulates Cholangiocarcinoma Mass Expansion and Tumor Dissemination under Growth-suppressive Peritumoral Myofibroblasts JF - bioRxiv DO - 10.1101/2023.01.24.525379 SP - 2023.01.24.525379 AU - Cheng Tian AU - Liyuan Li AU - Qingfei Pan AU - Beisi Xu AU - Yizhen Li AU - Li Fan AU - Anthony Brown AU - Michelle Morrison AU - Kaushik Dey AU - Jun J. Yang AU - Jiyang Yu AU - Evan S Glazer AU - Liqin Zhu Y1 - 2023/01/01 UR - http://biorxiv.org/content/early/2023/01/24/2023.01.24.525379.abstract N2 - Intrahepatic cholangiocarcinoma (iCCA) is characterized by its highly desmoplastic stroma. Myofibroblasts (MFs) are present both within the tumor mass (intratumoral MFs, iMFs) and at the tumor border (peritumoral MFs, pMFs). Using a spheroid-based coculture system, we show that the initial iCCA-pMF contact is growth suppressive to the tumor cells. However, prolonged iCCA-pMF interaction elicits significant tumor cell invasion and dissemination. We find that vascular cell adhesion molecule-1 (Vcam1) level is elevated in tumor cells in contact with pMFs but low in disseminated tumor cells both in vitro and in vivo. A gene regulatory network analysis of mouse and patient iCCA tumors and Vcam1 knockout (Vcam1KO) demonstrate a heavy involvement of Vcam1 in epithelial-to-mesenchymal transition. While Vcam1KO has only a limited impact on tumor cell growth in their monoculture, Vcam1KO spheroids exhibit instant dissemination and a severe growth defect when cocultured with pMFs. When transplanted into the liver, Vcam1KO iCCA cells show a similar increase in dissemination but a significant defect in establishing primary and metastatic tumors. Incomplete blocking of Vcam1 in vivo reduces the size but increase the number of metastatic lesions. Overall, our study shows a spatiotemporal regulation of iCCA growth and dissemination by pMFs in a Vcam1-dependent manner.Competing Interest StatementThe authors have declared no competing interest.iCCAintrahepatic cholangiocarcinomaeCCAextrahepatic cholangiocarcinomaHCChepatocellular carcinomaMFmyofibroblastpMFperitumoral myofibroblastiMFintratumoral myofibroblastCAFcancer-associated fibroblastHSChepatic stellate cellspHCperitumoral hepatocytesDTCdisseminated tumor cellsPPTRProm1CreERT2; Ptenflx/flx; Tp53flx/flx; Rosa-ZsGreenB6C57BL/6JZsGRosa-ZsGreentdTRosa-tdTomatoRFPRed Fluorescent ProteinGFPGreen Fluorescent ProteinCMconditioned mediaTVItail vein injection ER -