DDR2 induces linear invadosome to promote angiogenesis in a fibrillar type I collagen context

Abstract

To generate new vessels, endothelial cells (ECs) form invadosomes, which are actin-based microdomains with a proteolytic activity that degrade the basement membrane. We previously demonstrated that ECs form linear invadosomes in fibrillar type I collagen context. In this study, we aim to investigate the molecular mechanisms by which ECs guides angiogenesis in a fibrillar type I collagen context. We found that Discoidin Domain Receptor 2 (DDR2) is the collagen receptor tyrosine kinase required to form linear invadosomes in ECs. We further demonstrated that it acts in synergy with VEGF to promote extracellular matrix degradation.We highlighted the involvement of an interaction between DDR2 and the matrix metalloproteinase MMP14 in this process. Finally, using in vitro and ex-vivo angiogenesis assays, we demonstrated a pro-angiogenic function of DDR2 in a collagen-rich microenvironment. This study allows us to propose DDR2-dependent linear invadosomes as targets to modulate angiogenesis.

The Yin and Yang of Discoidin Domain Receptors (DDRs): Implications in Tumor Growth and Metastasis Development

“…DDR2 is required to elaborate linear invadosomes in endothelial cells and to facilitate matrix degradation in association with VEGF (Vascular Endothelial Growth Factor), but it is not known if DDR2 plays the same role in cancer cells [ 93 ]. Table 2 summarizes the different roles of DDRs in MMP activation and invadosome formation.…”

Collagen and Discoidin Domain Receptor 1 Partnership: A Multifaceted Role in the Regulation of Breast Carcinoma Cell Phenotype

“…Currently, the only study reported on DDR2 and linear invadosome concern endothelial cells. It is known that DDR2 can be involved in tumor progression through the tumor neo-angiogenesis process ( Abou Hammoud et al, 2020 ). In fact, the ECM degradation is necessary for the formation of new vessels in this process.…”