Spatiotemporal Dynamics of Vcam1 Regulates Cholangiocarcinoma Mass Expansion and Tumor Dissemination under Growth-suppressive Peritumoral Myofibroblasts
Oncogene(2023)
摘要
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 ( Vcam1 KO ) demonstrate a heavy involvement of Vcam1 in epithelial-to-mesenchymal transition. While Vcam1 KO has only a limited impact on tumor cell growth in their monoculture, Vcam1 KO spheroids exhibit instant dissemination and a severe growth defect when cocultured with pMFs. When transplanted into the liver, Vcam1 KO 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 Statement
The authors have declared no competing interest.
* iCCA
: intrahepatic cholangiocarcinoma
eCCA
: extrahepatic cholangiocarcinoma
HCC
: hepatocellular carcinoma
MF
: myofibroblast
pMF
: peritumoral myofibroblast
iMF
: intratumoral myofibroblast
CAF
: cancer-associated fibroblast
HSC
: hepatic stellate cells
pHC
: peritumoral hepatocytes
DTC
: disseminated tumor cells
PPTR
: Prom1CreERT2; Ptenflx/flx; Tp53flx/flx; Rosa-ZsGreen
B6
: C57BL/6J
ZsG
: Rosa-ZsGreen
tdT
: Rosa-tdTomato
RFP
: Red Fluorescent Protein
GFP
: Green Fluorescent Protein
CM
: conditioned media
TVI
: tail vein injection
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