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Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease., Author(s): Laura Broutier [1]; Gianmarco Mastrogiovanni [1, 2]; Monique MA Verstegen [3]; Hayley E Francies [4]; Lena Morrill Gavarró [2]; Charles R Bradshaw [1]; George E Allen [1]; Robert Arnes-Benito [...]

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the biliary tree and a risk factor for development of cholangiocarcinoma (CCA). The pathogenesis of PSC‐related CCA is largely unclear, although it is assumed that chronic inflammatory environment plays a pivotal role. We aimed to investigate the effect of inflammation‐related cytokines in PSC on the proliferation rate of cancer cells. For this, the proliferation index in PSC‐CCA and sporadic CCA was determined by Ki‐67 immunohistochemistry. The percentage of Ki‐67 positivity in cancer cells was significantly higher in PSC‐CCA than in sporadic CCA (41.3% ± 5.7% vs 25.8% ± 4.1%; P =.038). To assess which cytokines in the inflammatory environment have the potential to stimulate cancer cell proliferation, patient‐derived CCA organoids (CCAOs) were exposed to five cytokines related to PSC (Interleukin (IL)‐1β, IL‐6, IL‐17A, interferon gamma and tumor necrosis factor alpha). Only IL‐17A showed a significant stimulatory effect on cell proliferation in CCAOs, increasing organoid size by 45.9% ± 16.4% (P <.01) and proliferation rate by 38% ± 16% (P <.05). IL‐17A immunohistochemistry demonstrated that PSC‐CCA might express more IL‐17A than sporadic CCA. Moreover, correlation analysis in sporadic CCA and PSC‐CCA found a significant correlation between IL‐17A expression and proliferation. In conclusion, tumor cell proliferation is increased in PSC‐CCA cells compared with sporadic CCA cells. IL‐17A increases CCA cell proliferation in vitro and may contribute to the high proliferation rate in PSC‐CCA in situ. Therefore, IL‐17A represents a new potential therapeutic target in (PSC‐)CCA, to be tested in future trials. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming universally occurs in cancer. Mitochondria act as the hubs of bioenergetics and metabolism. The morphodynamics of mitochondria, comprised of fusion and fission processes, are closely associated with mitochondrial functions and are often dysregulated in cancer. In this study, we aim to investigate the mitochondrial morphodynamics and its functional consequences in human liver cancer. We observed excessive activation of mitochondrial fusion in tumor tissues from hepatocellular carcinoma (HCC) patients and in vitro cultured tumor organoids from cholangiocarcinoma (CCA). The knockdown of the fusion regulator genes, OPA1 (Optic atrophy 1) or MFN1 (Mitofusin 1), inhibited the fusion process in HCC cell lines and CCA tumor organoids. This resulted in inhibition of cell growth in vitro and tumor formation in vivo, after tumor cell engraftment in mice. This inhibitory effect is associated with the induction of cell apoptosis, but not related to cell cycle arrest. Genome-wide transcriptomic profiling revealed that the inhibition of fusion predominately affected cellular metabolic pathways. This was further confirmed by the blocking of mitochondrial fusion which attenuated oxygen consumption and cellular ATP production of tumor cells. In conclusion, increased mitochondrial fusion in liver cancer alters metabolism and fuels tumor cell growth. [ABSTRACT FROM AUTHOR]