ERK5 Mediates Metastatic Colonization and Remodeling of The Tumor and Tumor-Immune Microenvironment and Immunotherapy Response

ERK5 plays diverse roles in cancer progression including proliferation, epithelial-mesenchymal transition, and metastasis. We recently reported that different subcellular localizations of active phosphorylated-ERK5 (pERK5) in cancer cell lines and patient tumors associated with different molecular features and survival outcomes in breast cancer. We also showed that shorter isoforms of ERK5 play an important role in the nucleocytoplasmic shuttling of pERK5. In this study, we used in vitro and in vivo models to further understand the role of ERK5 in colonizing distant metastatic sites, and how ERK5 modulates pathways involved in the tumor and the immune microenvironment. For clinical context, we used the TCGA pan-cancer data to interrogate the correlation between pathways identified from our experimental studies and the expression of ERK5 and ERK5 isoforms in patients. We found that ERK5 is essential for colonizing metastatic sites in mice by mediating cell migration and invasion, remodeling the extracellular matrix (ECM) and regulating oncogenic and immune signaling pathways. The situation of ERK5 as a key protein in the crossroads between growth factor signaling, cytokine signaling, ECM remodeling and other functions was supported by strong correlations in the TCGA pan-cancer data between those pathways and the expression of ERK5 and ERK5 isoforms. Consequently, we validated our findings experimentally where we show that ERK5-depleted tumors in mice have denser collagen fibers suggesting a defect in ECM degradation and remodeling, have higher CD8 and CD4 T-cell infiltration and lower expression of PD-L1, and although they grow similarly to ERK5 wild-type tumors, ERK5-depleted were significantly sensitized to anti-PD1 immunotherapy. Our study supports a major role for ERK5 in the remodeling of the tumor and tumor-immune microenvironment that drives aggressive behavior thus could be a potential target for rationalized combination therapy.