Pathogenesis roles and therapeutic targets of PBRM1 mutation in intrahepatic cholangiocarcinoma

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We have created 12 lines of intrahepatic cholangiocyte organoids (iCO)from non-tumor livers and optimized conditions for CHO and intrahepatic cholangiocarcinoma organoids (iCCAO). Normal iCOs were grown well in our culture condition with ROCK Inhibitor (Y-27632) and R-Spondin, without Wnt3a. We have created 03 iCCA cell lines with PBRM1 knockout (KO), performed step-by-step TP53 and PBRM1 KO on normal iCOs, and established TP53-KO iCO, and double TP53 and PBRM1-KO iCOs, using CRISPR/Cas9.A novel TME classification of iCCA has been established, including four subtypes, showing distinct organizing patterns of T cells, myeloid cells, CAFs, an extracellular matrix such as collagen, and gene expression on spatial proteomic profiling, including CTLA4, PD-1, VISTA, LAG3, and TAGLN.