Pericytes orchestrate a tumor-restraining microenvironment in glioblastoma

Abstract Glioblastoma (GBM) is characterized by fast progression, infiltrative growth pattern, and a high relapse rate. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, where malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment. Here, we identify pericytes as the most active paracrine signaling hub within the tumor parenchyma. Their depletion through genetic engineering results in accelerated tumor progression and shortened survival. Mechanistic studies reveal that pericyte deficiency remodels the endothelium and impacts the immune cell landscape, exacerbating tumor cell invasion and immune suppression. Specifically, the pericyte-deprived endothelium recruits perivascular, tumor-associated macrophages polarized towards an immune-suppressive phenotype. The recruited macrophages express Hepatocyte Growth Factor, which reinforces activation of its receptor tyrosine kinase MET on GBM cells harboring a pronounced mesenchymal subtype driven by the key phenotypic regulator Fosl1 . Indeed, orthotopic implantation of MET-expressing GBM cells corroborates their superior tumor-initiating and invasive capabilities. Thus, pericytes represent critical modulators of GBM development by orchestrating a tumor-suppressive microenvironment, highlighting the importance of their preservation in therapy.