Work

The Portrait of Liver Cancer is Shaped by Mitochondrial Genetics

Year: 2021

Type: article

Abstract: Cancer heterogeneity and evolution combined with an equally dynamic immune microenvironment represent the main barriers to therapeutic success. This complexity is likely to have multiple origins, which are not fully understood. Here, we present data suggesting that mitochondrial DNA haplotype of the normal liver shapes tumor progression, burden, histology and the micro- and immune- environment prior to the acquisition of any oncogenic mutation. Using conplastic mice, we show that mtDNA dictates whether or not the mitochondrial unfolded protein response (UPRmt) is activated in the normal liver. Expression of Myc in combination with inhibition of p53 in UPRmt positive liver results in increased tumor incidence, burden and histological heterogeneity compared to UPRmt negative livers. Further, we found that a sub-set of UPRmt positive mice develop invasive liver cancers. RNA seq analysis of the normal liver revealed that in this subset of mice, the PAPP-A/DDR2/SNAIL axis of invasion pre-exists along with elevated collagen deposition. Since the protease PAPP-A was recently shown to promote immune evasion, we analyzed the immune signature in this subset of mice and found their livers to be immunosuppressed compare to the others. Further, the PAPP-A signature identifies the immune exhausted sub-set of HCC in humans. Our data suggest that the mitochondrial haplotype of normal liver establishes the landscape that shapes the entire liver cancer portrait upon acquisition of oncogenic mutations.Funding Information: This work was supported by an RO1 AG059635 award from the NIH to DG.Declaration of Interests: The authors have no conflicts of interest to declare.Ethics Approval Statement: All animal experiments were performed under an IUCAC approved protocol.

Source: Cell Reports

DOI: 10.1016/j.celrep.2021.110254