The Anticoagulant Protein S Mediates Tumor - Microenvironment Interactions Impacting Tumor Metastasis

Tumor development is critically impacted by inflammation created by distant and/or infiltrating immune cells in the tumor microenvironment (TME). A dynamic cross talk between cancer cells and the immune system is known to produce signaling pathways that mediate either a pro- or anti- tumorigenic effect. With respect to cancer, the receptor tyrosine kinases Tyro3, Axl, and MerTK (TAM family), are proto-oncogenes, found to be overexpressed and activated in various cancers, leading to increased tumor cell proliferation, migration, survival and drug - resistance. TAMs are also expressed by many immune cells, including macrophages, dendritic cells, natural killer (NK) cells and T cells, where they are important negative regulators of innate immunity. Here we investigate the role of the TAM agonist Protein S (PROS1) expressed by myeloid cells, in TME interactions, and its impact on metastasis. Our data indicate that mice lacking PROS1 in myeloid cells are susceptible to lung metastasis, suggesting a protective role for myeloid-derived PROS1. Moreover, in-vitro stimulation of Lewis Lung Carcinoma (LLC) cells with conditioned medium from PROS1-­deficient macrophages significantly increased the metastatic potential of LLC cells. These results reveal a mechanism by which macrophages affect tumor cell aggressiveness, and that this switch is regulated by PROS1. Interestingly, Pros1^-deficient macrophages exhibit a baseline pro-inflammatory profile.

Taken together, we speculate that deletion of myeloid­-derived PROS1 contributes to increased LLC tumor cell aggressiveness and at the same time to an elevated inflammatory milieu, rendering host cells permissive to metastatic colonization.

These studies warrant further investigation into the ongoing clinical implementation of TAM inhibitors for cancer therapy.