ABSTRACT
Glioblastoma (GBM) is the most aggressive intracranial malignancy with poor prognosis. Enhanced angiogenesis is an essential hallmark of GBM, which demonstrates extensive microvascular proliferation and abnormal vasculature. Here, we uncovered the key role of myosin 1b in angiogenesis and vascular abnormality in GBM. Myosin 1b is upregulated in GBM endothelial cells (ECs) compared to the paired non-malignant brain tissue. In our study, we found that myosin 1b promotes migration, proliferation and angiogenesis of human/mouse brain ECs. We also found that myosin 1b expression in ECs can be regulated by vascular endothelial growth factor (VEGF) signaling through myc. Moreover, myosin 1b promotes angiogenesis via Piezo1 by enhancing Ca2+ influx, in which process VEGF can be the trigger. In conclusion, our results identified myosin 1b as a key mediator in promoting angiogenesis via mechanosensitive ion channel component 1 (Piezo1) and suggested that VEGF/myc signaling pathway could be responsible for driving the changes of myosin 1b overexpression in GBM ECs.
ABSTRACT
The blood-brain barrier (BBB) serves as a crucial vascular specialization, shielding and nourishing brain neurons and glia while impeding drug delivery. Here, we conducted single-cell mRNA sequencing of human cerebrovascular cells from 13 surgically resected glioma samples and adjacent normal brain tissue. The transcriptomes of 103,230 cells were mapped, including 57,324 endothelial cells (ECs) and 27,703 mural cells (MCs). Both EC and MC transcriptomes originating from lower-grade glioma were indistinguishable from those of normal brain tissue, whereas transcriptomes from glioblastoma (GBM) displayed a range of abnormalities. Among these, we identified LOXL2-dependent collagen modification as a common GBM-dependent trait and demonstrated that inhibiting LOXL2 enhanced chemotherapy efficacy in both murine and human patient-derived xenograft (PDX) GBM models. Our comprehensive single-cell RNA sequencing-based molecular atlas of the human BBB, coupled with insights into its perturbations in GBM, holds promise for guiding future investigations into brain health, pathology, and therapeutic strategies.