BIOL-02. CELLULAR HETEROGENEITY CONTRIBUTES TO THE AGGRESSIVE BEHAVIOR OF MYC-DRIVEN MEDULLOBLASTOMA. (23rd April 2019)

• Record Type: Journal Article
• Authors: Qin, Nan; Langini, Maike; Picard, Daniel; Paisana, Eunice; Cascão, Rita; Custódia, Carlos; Meyer, Frauke; Stefanski, Anja; Stühler, Kai; Reifenberger, Guido; Borkhardt, Arndt; Faria, Cláudia; Remke, Marc
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 2
• Page Start: ii66
• Page End: ii66
• Publication Date: 2019-04-23
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz036.015
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: INTRODUCTION: Medulloblastoma is the most common malignant brain tumor of childhood and is a genetically heterogeneous disease. Amongst all medulloblastoma subgroups, MYC -amplified medulloblastomas are associated with a particularly poor prognosis as they are commonly metastatic and resistant to standard therapy. However, MYC amplification is restricted to a cellular subpopulation within MYC -amplified tumors. The underlying mechanisms mediating this cellular heterogeneity remain poorly understood. HYPOTHESIS: We hypothesize that a secretome-dependent crosstalk between MYC -amplified and non- MYC -amplified cells shapes an intratumoral microenvironment that promotes medulloblastoma aggressiveness. METHODS AND RESULTS: We first demonstrate that MYC overexpressing (high-MYC) cells induce proliferation and invasive growth patterns in their isogenic counterparts with low MYC expression (low-MYC) using contacting and non-contacting co-culture systems in three different medulloblastoma cell lines (ONS76, DAOY and UW228-3). Secondly, we demonstrate that exosomes from high-MYC cells promote the migratory propensity of low-MYC cells in vitro . Importantly, we confirmed the pro-tumorigenic interaction of high-MYC and low-MYC cells using two orthotopic medulloblastoma xenograft models. We further demonstrate that low-MYC cells promote tumor angiogenesis in vivo . Using an unbiased proteomic discovery approach and targeted validation by Western blotting, we identified and verified secreted proteins that may mediate this interaction. Rescue experiments validated the relevance of these candidates using functional genomics approaches in vitro, with in vivo validation being currently ongoing. CONCLUSION: We demonstrate that the crosstalk between cellular subclones in MYC-driven medulloblastoma may promote tumor growth, metastasis and angiogenesis. Understanding the underlying secretory signaling networks may elucidate novel therapeutic vulnerabilities in this prognostically poor subgroup of medulloblastoma.