Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages

Abstract

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 PRGN and shed TNFR2. 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 survival 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.

SPON2 Promotes M1-like Macrophage Recruitment and Inhibits Hepatocellular Carcinoma Metastasis by Distinct Integrin–Rho GTPase–Hippo Pathways

“…It is well-known that chemokines are involved in recruitments of monocytes/macrophages in cancer (40,41). Indeed, chemokine ligand 5 (CCL5) production was increased in HCC cells treated with rSPON2 comparing with controls ( Supplementary Fig.…”

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

“…These cytokines are primarily linked to monocyte recruitment and are known to be able to elevate TAM levels in tumors (Soria and Ben‐Baruch, 2008). Their role in modulating macrophage phenotype/functions is less clarified, although it has been demonstrated that CCL5 can promote prometastatic phenotype of TAMs (Frankenberger et al ., 2015). …”

Molecular Pathways: Targeting the Microenvironment of Liver Metastases

“…CCL5 is produced by CRC cells and by T cells at the margin of CRCLM (69). CCL5/CCR5 signaling has pleiotropic effects including recruitment of monocytes and M2 polarization, promoting the expansion of cancer-associated fibroblasts and enhancing TGFβ-mediated killing of CD8 + T cells by Treg (69, 70). A recent Phase 1 trial with a CCR5 antagonist demonstrated activity against advanced refractory CRCLM, identifying it as a target worthy of further clinical investigation (69).…”