Glioblastoma Multiforme & Angiogenesis

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Glioblastoma multiforme (GBM), or glioma, is a devastating and aggressive form of brain cancer. One of the central diagnostic features of GBM is a tortuous, leaky, and angiogenic vasculature. To date, anti-angiogenic therapies targeting either Vascular Endothelial Growth Factor, or its predominant angiogenic receptor VEGFR2, have failed to alter 5 year progression free survival in GBM patients. Our lab is currently attempting to more precisely define how the vasculature is affected during GBM progression, as well as post-chemotherapy. These studies are focused on the morphologic, functional, and transcriptional dynamics of endothelial behavior during GBM pre and post therapy, with the goal of identifying novel, targetable pathways or behaviors to reduce or halt GBM progression. Our first foray into this field, Carlson and Cantu Gutierrez et al., Neuro-Oncology, 2020 (click for details) (PMID: 33367832) showed that tumor stem cells contribute to the vascular endothelium and we identified extensive endothelial heterogeneity within the tumor vasculature using bulk and single cell RNA-seq and validated an angiogenic signature in human GBM. These studies are funded by the Cancer Prevention and Research Institute of Texas (CPRIT) (RP200402) and remain an ongoing focus in the lab as we test novel inhibitors of these angiogenic pathways to determine if they can slow tumor progression or improve survival in our native, immunologically competant mouse model.

Lightsheet confocal microscopy of a P80 mouse brain following vascular perfusion with fluorescent tomato lectin (teal) and CLARITY-based clearing. The magenta signal comes from in utero electroporation at E14.5 for a plasmid cocktail containing a Glast-driven pBase, a piggybac EGFP reporter, and CRISPR/Cas9 vector targeting Tp53, Pten, and Nf1 to induce glioma. From Carlson and Cantu Gutierrez et al., Neuro-Oncology, 2020.