| Summary: | <p>Cholangiocarcinoma is a highly aggressive cancer originating within the biliary tract. Whilst the role of the tumour microenvironment in CCA progression is well established, the function of surrounding cholangiocytes on CCA behaviour is often overlooked. Specifically, the effect of paracrine communication between cholangiocytes and cholangiocarcinoma cells has not been investigated previously. In this study, we provide evidence that cholangiocyte cells are a crucial paracrine modulator that influences the permissive or restrictive state to CCA progression.</p>
<p>Indirect co-culture of cholangiocarcinoma cells with cholangiocyte cells causes a significant decrease in CCA cell viability, migratory behaviour, and cell cycle progression, associated with a demonstratable switch in the gene and protein expression of the EMT markers E-cadherin, Slug, Snail, and Vimentin. Moreover, co-culture triggered a metabolic shift in CCA cells, with enhanced branched chain amino acid (BCAA) metabolism, as well as a transcriptomic shift resulting in increased cytokine signalling gene expression, recapitulated in the secretome.</p>
<p>In turn, cholangiocytes respond to this interaction with CCA cells, undergoing changes resulting in a growth advantage. Cholangiocytes experience an increase in creatine metabolism and ATP availability, linking to improved cell viability, increased cell cycle progression and reduced apoptosis, in conjunction with a reduction in gene and protein expression of p53 and apoptotic pathways.</p>
<p>Moreover, a high-throughput screen of epigenetic inhibitors successfully identified two targets, UNC0642 and SGC3027, for further development against CCA. More crucially, although effective against our CCA cell lines, co-culture with cholangiocytes caused a significant increase in IC50 value for these epigenetic inhibitors, implicating cholangiocyte cells in CCA chemoresistance.</p>
<p>We hypothesise the metabolic and genomic alterations triggered by this interaction contributes to CCA survival, invasiveness, and chemoresistance in the later stages of CCA development. Overall, our findings highlight the importance of cholangiocyte cells in modulating cholangiocarcinoma cells, impacting the development, progression, and treatment of cholangiocarcinoma.</p>
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