Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of pro-metastatic tumor-associated macrophages
Menée à l'aide de modèles murins de cancer du sein triplement négatif, cette étude met en évidence des mécanismes par lesquels, en régulant les macrophages associés aux tumeurs, la protéine RKIP réprime le processus invasif
Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. TNBC is characterized by reduced expression of metastasis suppressors such as Raf Kinase Inhibitory Protein (RKIP), which inhibits tumor invasiveness. Mechanisms by which metastasis suppressors alter tumor cells are well characterized; however, their ability to regulate the tumor microenvironment, and the importance of such regulation to metastasis suppression is incompletely understood. Here we use species-specific RNA sequencing to show that RKIP expression in tumors markedly reduces the number and metastatic potential of infiltrating TAMs. TAMs isolated from non-metastatic RKIP+ tumors, relative to metastatic RKIP- tumors, exhibit a reduced ability to drive tumor cell invasion and decreased secretion of pro-metastatic factors including shed TNFR2 and PGRN. RKIP regulates TAM recruitment by blocking HMGA2, resulting in reduced expression of numerous macrophage chemotactic factors, including CCL5. CCL5 overexpression in RKIP+ tumors restores recruitment of pro-metastatic TAMs and intravasation, while treatment with the CCL5 receptor antagonist Maraviroc reduces TAM infiltration. These results highlight the importance of RKIP as a regulator of TAM recruitment through chemokines such as CCL5. The clinical significance of these interactions is underscored by our demonstration that a signature comprised of RKIP signaling and pro-metastatic TAM factors strikingly separates TNBC patients based on outcome. Collectively, our findings identify TAMs as a previously unsuspected mechanism by which the metastasis suppressor RKIP regulates tumor invasiveness, and further suggest that TNBC patients with decreased RKIP activity and increased TAM infiltration may respond to macrophage-based therapeutics.