Necroptosis microenvironment directs lineage commitment in liver cancer

Abstract

Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC.

OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

“…This would suggest that MLKL-dependent necroptosis, eventually through a pathway independent of RIPK3, would protect OTULIN deficient hepatocytes from death by apoptosis. Interestingly, a recent study demonstrated that suppression of necroptosis in hepatocytes could promote hepatocyte apoptosis favoring the development of HCC (Seehawer et al, 2018). This observation suggested that hepatocyte necroptosis generates a liver cytokine microenvironment which promotes the development of intrahepatic cholangiocarcinoma and not HCC from oncogenically transformed hepatic cells (Seehawer et al, 2018).…”

Necroptosis in Cholangiocarcinoma

“…A recent study on mice addressed how a hepatic microenvironment, created by two different methods of oncogenic delivery, could influence the type of hepatic tumor [109]. The authors showed that the same oncogenic drivers delivered to mature hepatocytes gave rise to iCCA when embedded in a necroptosis-dominated microenvironment, while an apoptotic milieu favored the development of HCC [40,109]. The necroptosis microenvironment was characterized by specific inflammatory cytokines (e.g., C-C motif ligand 6) secreted from immune cells, which were, in turn, activated by DAMPs released from necroptotically dying hepatocytes [18,40,59].…”

Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective

“…(1) The regulatory molecules and tissue context that commit transformed hepatic cells toward HCC or CCA are still largely unknown, but a recent mouse study showed that hepatocytes with aberrantly activated oncogenes give rise to CCA when embedded in a necroptosis-dominated hepatic microenvironment. (65) DAMPs released by necroptotic hepatocytes can activate immune cells to secrete various specific cytokines to form a robust inflammatory environment, determining the outgrowth of CCA from transformed hepatocytes. In contrast, hepatocytes that harbor the same oncogenic driver will give rise to HCC if it is not adjacent to necroptotic hepatocytes.…”