biostudies-literatureQin NResearch Commission of the Medical Faculty, Heinrich Heine University Düsseldorf“Förderverein Löwenstern”Deutsche ForschungsgemeinschaftJosé-Carreras FoundationFundação Millennium bcp and Fundação Amélia de MelloGerman Cancer AidElterninitiative Kinderkrebsklinik1509-1523https://www.ebi.ac.uk/biostudies/studies/S-EPMC9435486biostudies-literatureUnknown24(9)<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.Neuro-oncologyIntratumoral heterogeneity of MYC drives medulloblastoma metastasis and angiogenesis.PMC9435486FOKO 2019-06KFO 337TRR205RE938/4-1CRC/TRR 205FOKO 2015-46RE 2857/2-1111537DJCLS 21R/2019Qin NPicard DBartl JRemke MLangini MBorkhardt ABlumel LCustodia CEisenhofer GFaria CCBechmann NBarata JTStefanski AMalzkorn BFischer UReifenberger GCascao RTaban KGobbels SPuget SPaisana EFelsberg JGravemeyer JStuhler KAyrault OMeyer FDConrad CBecker JCfalseIntratumoral heterogeneity of MYC drives medulloblastoma metastasis and angiogenesis.<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.2022-01-01T00:00:00Z2022 Sep2025-04-21T17:16:14.559Z2025-04-21T17:16:14.559ZS-EPMC94354863530774310.1093/neuonc/noac068