Tumor Associated Macrophages Promote Tumor Development through Remodeling of its Extracellular Matrix

Tumor-associated macrophages (TAM) are considered pivotal players in mounting pro-tumoral functions, yet, their effect on the tumor extracellular matrix (ECM) remains largely unclear. Here, using an orthotopic murine model of colorectal cancer (CRC) and advanced imaging techniques, we observed profound changes in ECM structure in the absence of TAM, namely in decreased content and linearization of cross-linked collagen fibers, a known hallmark of cancer. Proteomic analysis revealed major changes in ECM composition in TAM-deficient tumors and integrating transcriptomic and proteomic approaches we characterized a unique signature of ECM-remodeling enzymes and structural proteins expressed by sorted TAM. Finally, TAM-governed ECM modifications were pro-tumorigenic as decellularized 3D ECM fragments extracted from CRC WT tumors, but not from healthy colon or TAM-deficient tumors, enhanced cancer cell proliferation in-vitro and accelerated orthotopic tumor growth in-vivo. Overall, our results uncover new mechanistic insights of TAM-mediated remodeling of tumor ECM structure and composition.