Editors' ChoiceCancer

One hepatocyte, two malignant fates

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Science Translational Medicine  03 Oct 2018:
Vol. 10, Issue 461, eaav3884
DOI: 10.1126/scitranslmed.aav3884


Hepatic microenvironment dictates lineage commitment of hepatocytes, which can form two completely distinct tumor types.

One of the greatest mysteries in cancer biology is how a specific cell type generates diverse tumor types. Different mutations have been shown to affect lineage commitment and, therefore, the resulting tumor. However, the role of the microenvironment in determining the fate of a premalignant cell has not been established. This question is particularly relevant for those tumor types, such as primary liver tumors, that arise amidst a damaged and inflammatory microenvironment. In a recent study, Seehawer et al. demonstrate that the hepatic microenvironment epigenetically shapes lineage commitment of hepatocytes to give rise to either hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC), two distinct forms of primary liver cancer.

Hepatocytes can originate both HCCs and ICCs. By performing hydrodynamic tail vein (HTV) injection or electroporation, hepatocytes can be transfected in vivo with transposable elements that express key oncogenic drivers. In this study, HTV injection of oncogenic Myc and NrasG12V into p19-null mice led to the development of HCC, whereas electroporation of the same oncogenes unexpectedly formed ICC. The authors performed an exhaustive characterization to demonstrate that microenvironment damage was the cause. In particular, apoptosis of surrounding hepatocytes correlated with HCC development, whereas necroptosis caused by electroporation accompanied ICC. Accordingly, necroptosis inhibition before electroporation resulted in HCC instead of ICC. Mechanistically, TBX3 and PRDM5 were found to be epigenetically regulated by the microenvironment and to affect lineage commitment into HCC and ICC, respectively. Most importantly, in a cohort of 199 cases of human HCC and ICC, an apoptosis signature was found in HCC patients, whereas a necroptosis signature was enriched in ICC.

This study demonstrates that microenvironment damage can dictate the fate of cells in forming one tumor type or another. Besides the conceptual innovation, this study could have important therapeutic implications. First, it may allow predicting the development of HCC or ICC in patients with liver damage, which in turn could affect therapeutic decisions. Second, HCCs and ICCs expressing identical genetic alterations may have different therapeutic vulnerabilities. Future studies should help elucidate whether certain oncogenic drivers, such as MYC, are more prone to favor hepatocyte plasticity, or whether other oncogenes can behave similarly.

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