What causes liver cancer and what makes it vulnerable?

Hepatocellular carcinoma (HCC), which is the most common form of liver cancer, arises in the background of chronic inflammation. This complex process results in extensive tumor heterogeneity, which makes the design of therapeutic strategies exploiting genetic alterations of tumor cells extremely challenging. Hepatic stellate cells (HSC) promote HCC progression and are recognized as central players in controlling an inflammatory liver microenvironment conducive to tumor progression. This highlights the importance of developing innovative therapies that target the tumor microenvironment instead of oncogene-specific approaches. As there are no effective treatments for HCC, a better understanding of the cellular and molecular mechanisms central to liver inflammation development will cover a major gap in the field. Our laboratory has recently identified the autophagy and signaling adaptor p62/SQSTM1 as a critical negative regulator of HSC activation and a positive regulator of the oncogenic signals that promote tumorigenic pathways in hepatocytes. We showed that while p62 is upregulated in hepatocytes, it is reduced in HSCs in mouse and human HCC. Our studies unveiled the mechanisms whereby p62, and its PB1-interacting partner, PKCl/i, communicate to modulate the metabolism of liver cancer cells. Our understanding of how the cells in the surrounding microenvironment modulate these mechanisms still is fragmentary but are critical for the design of new therapeutic strategies harnessing the immune system to eradicate HCC cells.

Nishimura S, Linares JF, L'Hermitte A, Duran A, Cid-Diaz T, Martinez-Ordoñez A, Ruiz-Martinez M, Kudo Y, Marzio A, Heikenwalder M, Roberts LR, Diaz-Meco MT, Moscat J. (2024). Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma. Mol Cell. 84(23), 4660-4676.e10.

Kudo, Y., Sugimoto, M., Arias, E., Kasashima, H., Cordes, T., Linares, J.F., Duran, A., Nakanishi, Y., Nakanishi, N., L'Hermitte, A., Campos, A., Senni, N., Rooslid, T., Roberts, L.R., Cuervo, A.M., Metallo, C.M., Karin, M., Diaz-Meco, M.T., and Moscat, J. (2020). PKCl/i Loss Induces Autophagy, Oxidative Phosphorylation, and NRF2 to Promote Liver Cancer Progression. Cancer Cell 38, 247-262 [Highlighted in a Preview in the same issue of Cancer Cell]

Duran, A., Hernandez, E.H, Reina-Campos, M, Castilla, E.A., Subramaniam, S., Raghunandan, S., Roberts, L.R., Kisseleva, T., Karin, M., Diaz-Meco, M.T., Moscat, J. (2016) p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis and liver cancer. Cancer Cell 30, 595-609. PMC5081228 [“Free Featured Article” and Highlighted in a Preview in the same issue of Cancer Cell; and the Editor’s Choice section of Science Signaling]

Umemura, A., He, F., Taniguchi, K., Nakagawa, H., Yamachika, S., Font-Burgada, J., Zhong, Z., Subramaniam, S., Raghunandan, S., Duran, A., Linares, J.F., Reina-Campos, M., Umemura, S., Valasek, M.A., Seki, E., Yamaguchi, K., Koike, K., Itoh, Y., Diaz-Meco, M.T., Moscat, J.*, and Karin, M* (2016). p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 29, 935-948. PMC4907799 (*) Co-corresponding authors [Cover of issue and chosen as “Best of Cancer Cell 2016” article]