Platelet-Derived PDGFB Promotes Recruitment of Cancer-Associated Fibroblasts, Deposition of Extracellular Matrix and Tgfβ Signaling in the Tumor Microenvironment

SIMPLE SUMMARY: The aim of this study was to investigate the relative contribution of PDGFB derived specifically from platelets to the remodeling of the extracellular matrix (ECM) in tumors. Platelets are a major source of growth factors, which are released from the platelet granules upon activation. Platelets are continuously activated in the tumor microenvironment, due to their similarities to a wound. However, the role of platelet-derived factors in ECM remodeling has not been fully addressed. To this end, we made use of a mouse model with conditional deletion of PDGFB in platelets, which was crossbred to the RIP1-Tag2 model for pancreatic neuroendocrine carcinoma. The amount of tumor-associated PDGFB protein showed a 10-fold reduction in mice lacking PDGFB in platelets. Moreover, ECM deposition, the amount of cancer-associated fibroblasts and TGFβ signaling were all reduced in tumors from mice with platelet-specific deletion of PDGFB, demonstrating the significant contribution of a platelet-derived factor to ECM remodeling in tumors. ABSTRACT: Platelets constitute a major reservoir of platelet-derived growth factor B (PDGFB) and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth factors contained in platelet granules. To address the specific role of platelet-derived PDGFB in the tumor microenvironment, we have created a mouse model with conditional knockout of PDGFB in platelets (pl-PDGFB KO). Lack of PDGFB in platelets resulted in 10-fold lower PDGFB concentration in the tumor microenvironment, fewer cancer-associated fibroblasts and reduced deposition of the extracellular matrix (ECM) molecules fibronectin and collagen I in the orthotopic RIP1-Tag2 model for pancreatic neuroendocrine cancer. Myosin light chain phosphorylation, promoting cell contraction and, consequently, the mechano-induced release of active transforming growth factor (TGF) β from extracellular compartments, was reduced in tumors from pl-PDGFB KO mice. In agreement, TGFβ signaling, measured as phosphorylated Smad2, was significantly hampered in tumors from mice lacking PDGFB in their platelets, providing a plausible explanation for the reduced deposition of extracellular matrix. These findings indicate a major contribution of platelet-derived PDGFB to a malignant transformation of the tumor microenvironment and address for the first time the role of PDGFB released specifically from platelets in the remodeling of the ECM in tumors.