MBRS-53. CONTROL OF MEDULLOBLASTOMA VASCULATURE BY A REGULATOR OF NEUROGENESIS. (4th December 2020)

• Record Type: Journal Article
• Authors: Shaik, Shavali; Maegawa, Shinji; Haltom, Amanda; Dobson, Tara; Schadler, Keri; Gopalakrishnan, Vidya
• Is Part Of: Neuro-oncology. Volume 22(2020)Supplement 3
• Page Start: iii407
• Page End: iii407
• Publication Date: 2020-12-04
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noaa222.559
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Medulloblastomas are characterized by poor neuronal lineage specification. Expression of the RE1 Silencing Transcription Factor ( REST ), a regulator of neurogenesis, is aberrantly elevated in human sonic hedgehog (SHH) medulloblastomas. Using a novel transgenic mouse ( REST TG ) model, we demonstrated that REST is a driver of medulloblastoma genesis and promotes tumor progression in mice with loss of an allele of Ptch1 ( Ptch +/− ). Tumor formation in Ptch +/− /REST TG mice occurred with 100% penetrance and a latency of 10–90 days in contrast to Ptch +/− mice, which developed tumors at a frequency of 15–20% at 6–9 months of age. Histopathological analyses showed leptomeningeal dissemination of tumors in Ptch +/− /REST TG mice, in addition to a significant increase in tumor vasculature compared to tumors in Ptch +/− mice. These findings were recapitulated in xenografted tumors of isogenic low and high-REST medulloblastomas in mice. Proteome profiler human angiogenesis array analyses revealed a REST-dependent increase in vascular endothelial growth factor (VEGF) and placental growth factor (PLGF). Surprisingly, REST elevation also caused co-localization of tumor cells with tumor vasculature, specifically endothelial cells, and was associated with upregulated expression of a number of pro-angiogenic genes, including receptor VEGFR1 and the positive regulator of endothelial differentiation, E26 transformation specific-1 ( ETS1 ), in tumor cells. In addition, expression of several anti-angiogenic molecules was downregulated. Knockdown of ETS1 reversed the above findings. Thus, our data demonstrate that REST elevation not only blocks neurogenesis in medulloblastoma cells, but also modulates the tumor microenvironment by mechanisms that likely involve vascular mimicry.