Abstract IA23: Medulloblastoma subgroup-specific mutations model the tumor microenvironment

Abstract:

Abstract Brain tumors, especially those arising in children, are remarkably heterogeneous in their response to treatment. Understanding the processes that dictate treatment sensitivity is important if we are to cure all patients. Most research has focused on identifying tumor cell intrinsic properties that regulate treatment response; but the role of the tumor microenvironment is less well understood. Here, we show that distinct subtypes of medulloblastoma possess markedly different vasculatures that are determined non-autonomously by tumor genotype, and that dictate response to systemic chemotherapy. We found that WNT-antagonists secreted by WNT-medulloblastoma – an essentially curable form of the disease – silence WNT signaling in neighboring endothelial cells, causing the formation of fenestrated and highly permeable vessels normally associated with peripheral organs: endothelial WNT signaling is essential to form and maintain the blood brain barrier (BBB). Consequently, systemically delivered chemotherapy accumulated to high levels in WNT-medulloblastomas, eliciting a marked clinical response. In contrast, while cells derived from Sonic Hedgehog (SHH)-medulloblastoma – a much less curable subtype – were intrinsically chemosenstive, they did not secrete WNT-antagonists, formed tumors with an intact, chemo-impermeable BBB and were chemoresistant in vivo. Remarkably, reactivation of WNT-signaling in WNT-medulloblastoma endothelial cells restored BBB function, rendering these tumors chemoresistant. Our data provide direct evidence that brain tumor genotype can dictate tumor vessel phenotype in a non-autonomous fashion, providing a potential explanation for the excellent prognosis of WNT-medulloblastoma. Pharmacological inhibition of endothelial WNT signaling in other primary and secondary brain tumors might enhance chemoresponsiveness by disrupting the BBB. Citation Format: Richard J. Gilbertson. Medulloblastoma subgroup-specific mutations model the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA23.

Authors:

RJ Gilbertson

Journal:

Cancer Research

Citation info:

75(23_Supplement):ia23-ia23

Publication date:

1st Dec 2015

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