Eichmann, A. — Page 2 | bioRxiv Science

bioRxiv2021

SLIT2-ROBO signaling in tumor-associated microglia/macrophages drives glioblastoma immunosuppression and vascular dysmorphia

SLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient derived GBM xenografts reduced tumor growth and synergized with immunotherapy to prolong survival. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1&2-mediated PI3K{gamma} activation. Macrophage Robo1&2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a novel regulator of the GBM microenvironment and a potential immunotherapeutic target for brain tumors.

cancer biology↗

bioRxiv2019

Activation of Smad 2/3 signaling by low shear stress mediates artery inward remodeling

RationaleBlood vessel remodeling in response to changes in tissue demand is an important aspect of fitness and is often compromised in vascular disease. Endothelial cell (EC) sensing of fluid shear stress (FSS) governs vessel remodeling to maintain FSS at a specific magnitude or set point in healthy vessels.\n\nObjectiveThe purpose of this study was to understand how shear stress-regulated Smad 2/3 contributes to artery remodeling.\n\nMethods and ResultsWe found that shear stress induces Smad 2/3 phosphorylation, nuclear translocation, and gene expression in ECs. Nuclear translocation and gene expression are maximal at low and decrease at high FSS. Reducing flow in the mouse carotid by ligation of branch vessels induces Smad2 nuclear localization in vivo. Activation of Smad 2/3 by FSS requires the Type I TGF{beta} family receptor Alk5 and the transmembrane protein Neuropilin-1. Flow activation of Smad 2/3 is mediated by increased sensitivity to BMP9 but not BMP10 or TGF{beta}. By contrast, flow activation of Smad 1/5 is maximal at physiological FSS and requires BMP9 or 10 binding to Alk1 and Endoglin. EC-specific deletion of Alk5 in mice blocks low flow-induced inward remodeling after carotid ligation.\n\nConclusionsTogether, these data elucidate a novel pathway that mediates low flow-induced inward artery remodeling. These results may be relevant to inward remodeling in diseased vessels where Smad 2/3 is activated by pathological stimuli.

cell biology↗