Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma

Abstract

Human cholangiocarcinoma (CCA) is an aggressive tumour entity arising from the biliary tree, whose molecular pathogenesis remains largely undeciphered. Over the last decade, the advent of high‐throughput and cell‐based techniques has significantly increased our knowledge on the molecular mechanisms underlying this disease while, at the same time, unravelling CCA complexity. In particular, it becomes clear that CCA displays pronounced inter‐ and intratumoural heterogeneity, which is presumably the consequence of the interplay between distinct tissues and cells of origin, the underlying diseases, and the associated molecular alterations. To better characterize these events and to design novel and more effective therapeutic strategies, a number of CCA experimental and preclinical models have been developed and are currently generated. This review summarizes the current knowledge and understanding of these models, critically underlining their translational usefulness and limitations. Furthermore, this review aims to provide a comprehensive overview on cells of origin, cancers stem cells and their dynamic interplay within CCA tissue.

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

“…Tumour spheroids are self-assembled cultures of cancer cells in the presence or absence of stromal cells within a hydrogel, mimicking the basement membrane, where cell-cell interactions predominate over cell-substrate interactions 241 . By contrast, tumour organoids are self-organizing stem cell-like structures cultured and expanded in a hydrogel 76,242,243 . Organoids are successfully established from resected tissue biopsy and needle biopsy samples, faithfully recapitulating the patient tumour at the histopathological level, both in culture and as xenografts in immune-deficient mice 242,244 .…”

“…However, to recapitulate CCA tumours in vivo, organoids should be co-cultured with stromal cells. Importantly, whole-exome sequencing revealed that the vast majority of the mutations are retained in liver cancer organoids derived from resected tissues, whereas mutation retention is heterogeneous in biopsy-derived liver cancer organoids 76,242,243 . Furthermore, CCA organoids have been shown to be a reliable system for drug testing and personalized medicine applications, and possess an almost negligible capacity to differentiate into hepatocytes 76,245 .…”

“…In PSC, peribiliary gland cell proliferation, mucinous metaplasia, and dysplasia to cancer progression take place within bile ducts and along the biliary tree, mimicking the cancerization field ('field defect') 49,75 . Controversies exist regarding the cellular origins of iCCA based on lineage tracing studies in experimental carcinogenetic models 76 . Indeed, there is evidence in favour of HpSC, cholangiocyte or hepatocyte origin of iCCA from these experimental settings [76][77][78][79][80][81] .…”

“…Controversies exist regarding the cellular origins of iCCA based on lineage tracing studies in experimental carcinogenetic models 76 . Indeed, there is evidence in favour of HpSC, cholangiocyte or hepatocyte origin of iCCA from these experimental settings [76][77][78][79][80][81] . Thus, a definitive determination of the origin of iCCA in humans cannot be reached based on current evidence and requires further research.…”

Mitochondrial Fusion Via OPA1 and MFN1 Supports Liver Tumor Cell Metabolism and Growth

“…The obtained mycoplasma-free human cell lines were commercially checked monthly by GATC Biotech (GATC Biotech, Konstanz, Baden-Württemberg, Germany) and their identity verified by the molecular pathology department of the Erasmus MC as described previously [16]. Healthy liver, adjacent liver, and CCA organoids were cultured as previously described [17][18][19]. Informed consent was obtained from all patients and the use of patient materials was approved by the medical ethical committee of Erasmus Medical Center, Rotterdam (MEC-2014-060 and MEC-2013-143).…”