P02.01.B PERICYTES ORCHESTRATE A TUMOR-SUPPRESSIVE MICROENVIRONMENT BY IMPINGING ON THE CROSSTALK BETWEEN MACROPHAGES AND TUMOR-INITIATING CELLS IN GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is characterized by fast progression, infiltrative growth pattern and a high rate of relapse. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, i.e. a hypoxic niche, a leading-edge niche, and a peri-vascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment, including immune cells, astrocytes, and vascular cells. MATERIAL AND METHODS AND RESULTS By analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes intimately associated with the endothelium as the most active paracrine signaling hub within the tumor parenchyma. Exclusive signaling axes emanating from pericytes were received by endothelial cells, malignant cells, astrocytes, and immune cells. Depletion of pericytes through genetic engineering in several different transgenic and orthotopic mouse models of GBM demonstrated accelerated tumor progression, a disrupted blood-brain-barrier, and premature death of pericyte-poor mice. Mechanistic studies revealed that pericyte deficiency altered the cellular composition of GBM, remodeled the endothelium, and impacted on the immune cell landscape. Specifically, endothelial cells deprived of pericyte association upregulated Colony Stimulating Factor (CSF)-1, which in turn attracted peri-vascular tumor-associated macrophages polarized towards an immune-suppressive phenotype. In the absence of pericytes, the recruited macrophages expressed Hepatocyte Growth Factor (HGF), which reinforced activation of its receptor tyrosine kinase c-Met on a subset of GBM cells harboring an extreme mesenchymal-like state. Indeed, orthotopic implantation of isolated c-Met-expressing GBM cells corroborated their superior tumor-initiating capability and invasive phenotype, compared to cells negative for c-Met. CONCLUSION We infer that the pericyte represents a critical modulator of GBM development by orchestrating a tumor-suppressive microenvironment; our findings thus highlight the importance of pericyte preservation in the face of current and future GBM therapies.