While primary tumors are the consequence of the stepwise acquisition of oncogenic mutations in the epithelial compartment, increasing evidence demonstrates that the tumor microenvironment also plays a critical role in cancer progression. However, relatively little is known about the signaling and metabolic pathways that mediate the stromal-epithelium crosstalk. Inflammation and metabolism are two critical contributors to the pro-tumorigenic properties of the tumor stroma, which includes cancer-associated fibroblasts (CAFs). A common theme underlying all the projects in our laboratories is based on the many striking contributions that we have made to help in our understanding of these processes in prostate, liver and colorectal cancer. For example, we showed that p62/SQSTM1, working independently of its function as an autophagy adaptor, repressed metabolic and inflammatory pathways in CAFs that control prostate cancer progression under conditions of nutrient stress in the microenvironment. p62/SQSTM1 also played a major role in the liver stroma by modulating the activity of the vitamin D receptor. These observations reveal a central role of stromal p62 in the symbiotic collaboration between CAFs and epithelial cells that enables cancer metabolic fitness and the control of the pro-tumorigenic inflammatory microenvironment. Interestingly, we have also shown recently that the PB1-containing kinase, PKCz, is a repressor of CAF activation and heterogeneity through the regulation of the master lineage transcriptional factor SOX2. How the upregulation of stromal SOX2 precisely promotes the lineage plasticity in the stroma, required to drive the metastatic stage of colorectal cancer cells, is an outstanding question whose resolution will result in the identification of new therapeutic targets in the tumor microenvironment for the treatment of different types of cancers.

Kasashima, H., Duran, A., Martinez-Ordonez, A., Nakanishi, Y., Kinoshita, H., Linares, J.F., Reina-Campos, M., Kudo, Y., L'Hermitte, A., Yashiro, M., Ohira, M., Bao, F., Tauriello, D.V.F., Batlle, E., Diaz-Meco, M.T., and Moscat, J. (2020). Stromal SOX2 Upregulation Promotes Tumorigenesis through the Generation of a SFRP1/2-Expressing Cancer-Associated Fibroblast Population. Developmental Cell 56, 95-110, 2021. PMID: 33207226 [“Free Featured Article” and Highlighted in a Preview in the same issue of Developmental Cell]

Linares, J.F., Cordes, T., Duran, A., Reina-Campos, M., Valencia, T., Ahn, C.S., Castilla, E.A., Moscat, J., Metallo, C.M., Diaz-Meco, M.T. (2017). ATF4-induced metabolic reprograming is a synthetic vulnerability of the p62-deficient tumor stroma. Cell Metabolism 26, 818-829. PMC5718961

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]

Valencia, T., Kim, J.Y., Abu-Baker, S., Moscat-Pardos, J., Ahn, C.S., Reina-Campos, M., Duran, A., Castilla, E.A., Metallo, C.M., Diaz-Meco, M.T., and Moscat, J. (2014) Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell 26, 121-135. PMC4101061 [Highlighted in a Preview in the same issue and in Cancer Discovery and Nature Reviews in Cancer and chosen as “Best of Cancer Cell 2014” article]