Pericytes orchestrate a tumor-restraining microenvironment in glioblastoma

Abstract

Glioblastoma (GBM) is characterized by fast progression, an 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 perivascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment. Here, by analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes, mural cells 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, exacerbating tumor cell invasion and immune suppression. Specifically, endothelial cells deprived of pericyte association altered their signaling programs, which in turn attracted perivascular, tumor-associated macrophages polarized towards an immune-suppressive phenotype. The recruited macrophages expressed Hepatocyte Growth Factor (HGF), which reinforced activation of its receptor tyrosine kinase MET on GBM cells harboring an extreme mesenchymal subtype driven by the key phenotypic regulator Fosl1 within hypoxic regions. Indeed, orthotopic implantation of isolated, MET-expressing GBM cells corroborated their superior tumor-initiating capability and invasive phenotype. In patients, low expression of a pericyte core gene signature was reduced in recurrent GBM, compared to primary tumors. Consistently, gene signatures for transcriptional programs of Fosl1+Met+ GBM cells were indicative of poor survival in human tumors, and spatial transcriptomics corroborated their superior invasive capacity. Taken together, 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/609765v1_ufig1.gif" ALT="Figure 1"> View larger version (102K): org.highwire.dtl.DTLVardef@803a8eorg.highwire.dtl.DTLVardef@8441eaorg.highwire.dtl.DTLVardef@1038288org.highwire.dtl.DTLVardef@16eccfc_HPS_FORMAT_FIGEXP M_FIG C_FIG