Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver

Abstract

Hepatocellular carcinoma (HCC) is driven by repeated rounds of inflammation, leading to fibrosis, cirrhosis, and, ultimately, cancer. A critical step in HCC formation is the transition from fibrosis to cirrhosis, which is associated with a change in the liver parenchyma called ductular reaction. Here, we report a genetically engineered mouse model of HCC driven by loss of macroautophagy and hemizygosity of phosphatase and tensin homolog, which develops HCC involving ductular reaction. We show through lineage tracing that, following loss of autophagy, mature hepatocytes dedifferentiate into biliary-like liver progenitor cells (ductular reaction), giving rise to HCC. Furthermore, this change is associated with deregulation of yes-associated protein and transcriptional coactivator with PDZ-binding motif transcription factors, and the combined, but not individual, deletion of these factors completely reverses the dedifferentiation capacity and tumorigenesis. These findings therefore increase our understanding of the cell of origin of HCC development and highlight new potential points for therapeutic intervention.

Specificity and off-target effects of AAV8-TBG viral vectors for the manipulation of hepatocellular gene expression in mice

“…One limitation of our work is that we have not explored the longer term consequences of AAV8 use in WT animals. We have observed long term hepatic expression of GFP in mice at 100 days following AAV8- TBG -GFP administration ( Barthet et al, 2021 ). Persistent expression of AAV8- TBG -driven GFP in the liver suggests persistence of AAV8- TBG vectors in the hepatocytes.…”

DRAM‐4 and DRAM‐5 are compensatory regulators of autophagy and cell survival in nutrient‐deprived conditions

“…F‐410) on a Step‐One Plus (Applied Biosystems, Waltham, MA, USA) as follows: 20 s at 95 °C, followed by 40 cycles of 3 s at 95 °C, and 30 s at 60 °C. Methods adapted from our previous work [23]. mRNA quantification was calculated using the 2 −ΔΔCT method.…”

Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance

“…This paper will mainly focus on macro-autophagy and will subsequently use the convention of referring to this process as “autophagy.” Interestingly, there are two different roles for macro-autophagy reported in the literature. Lethal/toxic autophagy, also known as autophagic cell death, results in increased cell death, which has been reported in glioblastoma and HCC [ 50 , 51 ]. Conversely, protective autophagy is a major cause of survival and chemotherapy resistance in CSC populations [ 15 ].…”

“…Autophagy-deficient livers illustrated that strong YAP and TAZ co-expression induces ductular cell formation and carcinogenesis of HCC. Additionally, autophagy-deficient livers had significant accumulation of cleaved caspase-3 and ductular markers, including SOX9, cytokeratin 19, panCK, suggesting that autophagy prevents apoptosis in hepatocytes and undermines dedifferentiation of hepatocytes into LPCs [ 51 ] ( Table 2 ). Together, these studies support the idea that autophagy impedes CSC stemness and proliferation ( Figure 2 ).…”