MAPK Signaling Is Required for Generation of Tunneling Nanotube-Like Structures in Ovarian Cancer Cells

SIMPLE SUMMARY: Ovarian cancer is the 5th leading cause of cancer death in US women, due to late diagnosis. The vast majority of patients with ovarian cancer have metastatic disease at diagnosis, leading to poor survival. As the tumor cells metastasize, they are influenced by other cells they encounter. In particular, we found that macrophages induce a mechanism of communication in tumor cells called tunneling nanotubes. These tunneling nanotubes allow cells to share molecules that promote metastasis. We found that macrophages send signals to the tumor cells in order to activate oncogenic MAPKinase signaling, which is required for tunneling nanotubes to form. Our new understanding of these events will enable us to devise ways to target tunneling nanotubes and limit tumor spread. ABSTRACT: Ovarian cancer (OC) cells survive in the peritoneal cavity in a complex microenvironment composed of diverse cell types. The interaction between tumor cells and non-malignant cells is crucial to the success of the metastatic process. Macrophages activate pro-metastatic signaling pathways in ovarian cancer cells (OCCs), induce tumor angiogenesis, and orchestrate a tumor suppressive immune response by releasing anti-inflammatory cytokines. Understanding the interaction between immune cells and tumor cells will enhance our ability to combat tumor growth and dissemination. When co-cultured with OCCs, macrophages induce projections consistent with tunneling nanotubes (TnTs) to form between OCCs. TnTs mediate transfer of material between cells, thus promoting invasiveness, angiogenesis, proliferation, and/or therapy resistance. Macrophage induction of OCC TnTs occurs through a soluble mediator as macrophage-conditioned media potently induced TnT formation in OCCs. Additionally, EGFR-induced TnT formation in OCCs through MAPK signaling may occur. In particular, inhibition of ERK and RSK prevented EGFR-induced TnTs. TnT formation in response to macrophage-conditioned media or EGFR signaling required MAPK signaling. Collectively, these studies suggest that inhibition of ERK/RSK activity may dampen macrophage-OCC communication and be a promising therapeutic strategy.