CRISPR gene editing to create liver organoids with mutations underlying fibrolamellar carcinoma
Fibrolamellar carcinoma (FLC) is an often fatal liver cancer affecting young people. The molecular mechanisms driving it are unclear, partly because of a lack of experimental models. Researchers now create human liver organoids (pictured using fluorescent microscopy) of healthy liver tissue (top, left) and, using genetic engineering technology, CRISPR, those that replicate liver with the different genetic faults found in FLC. Most common is the fusion of genes DNAJB1 and PRKACA (top, right), and also found are faults in PRKAR2A and BAP1 genes separately and together (bottom, left to right). FLC organoids mimicked tumour samples from patients and their liver cells regressed to an immature state. However, only faulty BAP1 and PRKAR2A together caused liver cells to turn into progenitor-like cells that, unlike normal liver cells, could grow in liver ducts. Meanwhile, DNAJB1-PRKACA organoids showed milder cancer features compared with other FLC organoids. Together, these FLC models hold promise for studying FLC progression.
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