%0 Generic
%A Janzen, Jakob
%C Heidelberg
%D 2024
%F heidok:33614
%R 10.11588/heidok.00033614
%T Analysis of High-mobility Group A proteins in nonalcoholic steatohepatitis (NASH) and liver cancer
%U https://archiv.ub.uni-heidelberg.de/volltextserver/33614/
%X Liver cancer is the sixth most common type of cancer worldwide and the second leading cause of cancer-related death. Despite the improved management of viral-induced liver cancer, the number of patients is increasing due to the rising incidence of nonalcoholic steatohepatitis (NASH) and NASH-HCC. Since curative treatments are limited, the therapy goal is the prolongation of life span, while maintaining the quality of life. Therefore, it is of high priority to understand the underlying molecular mechanisms and the contribution of genes involved in prolonging or shortening the life span. Bulk tissue expression analysis has revealed, that expression of HMGAs on mRNA level correlates with poor survival in a variety of solid tumors including HCC and CCA. High mobility group A proteins function as architectural transcription factors by binding to the AT-rich regions in the minor groove of DNA. They transcriptionally regulate proteins that are linked to cell cycle control, DNA repair, and epithelial-mesenchymal transition. However, a spatially and temporarily resolved expression analysis in liver cancer taking into account different subtypes and etiologies was still missing. Here I show that in liver cancers, HMGAs are expressed in different cell types (parenchymal/non-parenchymal) and subcellular localizations (cytoplasm/nuclear). In HCCs elevated mRNA levels of HMGAs are mainly expressed at advanced tumor stages. Elevated expression is associated with increased proliferation, the presence of liver progenitor cells, and immunosuppression. In iCCAs elevated mRNA levels of HMGAs are expressed irrespective of the tumor stage. In preclinical liver cancer models elevated expression of HMGAs was found in advanced-stage tumors driven by distinct tumor driver combinations. More important, in diet-induced NASH-HCC expression of HMGAs could not be detected. Functional analysis of the contribution of HMGAs by genetic gain and loss of function studies in preclinical mouse models reveal that HMGAs contribute to cancer progression only within a certain context. I found that HMGA2 loss in hepatocytes delays NASH to HCC transition in a western diet model, and has no significant impact on liver metabolism or inflammation during NASH development. The ectopic expression of HMGAs alone is not sufficient to initiate liver neoplasias, while ectopic expression of HMGAs in the myr-AKT1/NICD1 mouse model for iCCA accelerates tumor progression. In mixed HCC/iCCA Trp53KO/KRASG12D-driven liver tumors, the loss of HMGAs has no significant effect on tumor progression. In summary, (1) HMGAs show distinct but complex spatially and temporally differentiated expression patterns in liver cancer, (2) a context-dependent mode of action and lack antitumorigenic effect upon HMGA depletion. Thus, targeting HMGAs is most likely not a promising future strategy to prolong the survival of liver cancer patients. However, the FDA-approved minor groove binding agent trabectedin acts antitumorigenic by impairing HMGA function, but also via other mechanisms. Here I report that trabectedin treatment reduces tumor growth and prolongs survival in the mixed HCC/iCCA model Trp53KO/KRASG12D, and the iCCA model myr-AKT1/NICD1, but not the HCC model Trp53KO/cMyc. Mechanistically, I found that trabectedin directly targets tumor cells by reducing proliferation by transcriptionally downregulating gene sets involved in oncogenic signaling. Moreover, trabectedin modulates the tumor microenvironment, enabling T-cell infiltration of treated tumors. The antitumorigenic effect of trabectedin monotherapy implies that trabectedin could be a promising complementary component to improve iCCA therapy. Future research is needed to further understand the molecular mechanisms of trabectedin in liver cancer, and to identify synergistically or additively acting therapies.