Intratumoral heterogeneity of MYC drives medulloblastoma metastasis and angiogenesis.

Jan Gravemeyer, Marc Remke, Claudia C Faria, Graeme Eisenhofer, Arndt Borkhardt, Guido Reifenberger, Olivier Ayrault, Jörg Felsberg, Ute Fischer, Kai Stühler, João T Barata, Stéphanie Puget, Anja Stefanski, Jürgen C Becker, Nan Qin, Catleen Conrad, Nicole Bechmann, Jasmin Bartl, Kübra Taban, Sarah Göbbels, Lena Blümel, Frauke-Dorothee Meyer, Rita Cascão, Carlos Custódia, Bastian Malzkorn, Daniel Picard, Maike Langini, Eunice Paisana

Journal: Neuro-oncology 2022;24(9):1509-1523

PMID: 35307743

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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.

Address: German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf , Düsseldorf, Germany.; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany.; Institute of Neuropathology, Medical Faculty, HHU, UKD, Düsseldorf, Germany.; Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.; Institute for Molecular Medicine I, Heinrich Heine University, University Hospital Düsseldorf , Düsseldorf, Germany.; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, and Technical University Dresden , Dresden, Germany.; Department of Medicine III, University Hospital Carl Gustav Carus, Technical University Dresden , Dresden, Germany.; Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.; German Center for Diabetes Research, München-Neuherberg, Germany.; Translational Skin Cancer Research, University Duisburg-Essen, Essen, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; Molecular Proteomics Laboratory, Biomedical Research Center (BMFZ), Heinrich Heine University, Medical Faculty, Düsseldorf, Germany.; Department of Pediatric Neurosurgery, Necker Hospital, Paris Descartes University, Paris, France.; Institut Curie, PSL Research University, Université Paris Sud, Université Paris-Saclay, Orsay, France.; Department of Neurosurgery, Hospital Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, Portugal.

DOI: 10.1093/neuonc/noac068

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MeSH Terms: Cerebellar Neoplasms, Humans, In Situ Hybridization, Fluorescence, Medulloblastoma, Prognosis, Proto-Oncogene Proteins c-myc