Intratumoral heterogeneity of MYC drives medulloblastoma metastasis and angiogenesis. Issue 9 (21st March 2022)

• Record Type: Journal Article
• Authors: Qin, Nan; Paisana, Eunice; Langini, Maike; Picard, Daniel; Malzkorn, Bastian; Custódia, Carlos; Cascão, Rita; Meyer, Frauke-Dorothee; Blümel, Lena; Göbbels, Sarah; Taban, Kübra; Bartl, Jasmin; Bechmann, Nicole; Conrad, Catleen; Gravemeyer, Jan; Becker, Jürgen C; Stefanski, Anja; Puget, Stéphanie; Barata, João T; Stühler, Kai; Fischer, Ute; Felsberg, Jörg; Ayrault, Olivier; Reifenberger, Guido; Borkhardt, Arndt; Eisenhofer, Graeme; Faria, Claudia C; Remke, Marc
• Is Part Of: Neuro-oncology. Volume 24:Issue 9(2022)
• Page Start: 1509
• Page End: 1523
• Publication Date: 2022-03-21
• Subjects: angiogenesis -- intratumoral heterogeneity -- medulloblastoma -- metastasis -- secretome; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac068
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: Intratumoral heterogeneity is crucially involved in metastasis, resistance to therapy, and cancer relapse. Amplifications of the proto-oncogene MYC display notable heterogeneity at the single-cell level and are associated with a particularly dismal prognosis in high-risk medulloblastomas (MBs). The aim of this study was to establish the relevance of interclonal cross-talk between MYC-driven and non-MYC-driven MB cells. Methods: We used fluorescence in situ hybridization, single-cell transcriptomics, and immunohistochemistry, in vitro isogenic cell models, non-targeted proteomics, mass spectrometry-based metabolite quantification, HUVECs tube formation assay, and orthotopic in vivo experiments to investigate interclonal cross-talk in MB. Results: We found that the release of lactate dehydrogenase A (LDHA) from MYC-driven cells facilitates metastatic seeding and outgrowth, while secretion of dickkopf WNT signaling pathway inhibitor 3 from non-MYC-driven cells promotes tumor angiogenesis. This tumor-supporting interaction between both subclones was abrogated by targeting the secretome through pharmacological and genetic inhibition of LDHA, which significantly suppressed tumor cell migration. Conclusion: Our study reveals the functional relevance of clonal diversity and highlights the therapeutic potential of targeting the secretome to interrupt interclonal communication and progression in high-risk MB. Graphical Abstract: