Nan Qin1,2,3, Eunice Paisana4, Maike Langini1,2,3,5, Daniel Picard1,2,3, Bastian Malzkorn3, Carlos Custódia4, Rita Cascão4, Frauke-Dorothee Meyer1,2,3, Lena Blümel1,2,3, Sarah Göbbels1,2,3, Kübra Taban1,2,3, Jasmin Bartl1,2,3, Nicole Bechmann6,7,8,9, Catleen Conrad6,7, Jan Gravemeyer10,11, Jürgen C Becker10,11, Anja Stefanski12, Stéphanie Puget13, João T Barata4, Kai Stühler5,12, Ute Fischer2, Jörg Felsberg3, Olivier Ayrault14, Guido Reifenberger1,3, Arndt Borkhardt2, Graeme Eisenhofer6,7, Claudia C Faria4,15, Marc Remke1,2,3. 1. German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf , Düsseldorf, Germany. 2. Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany. 3. Institute of Neuropathology, Medical Faculty, HHU, UKD, Düsseldorf, Germany. 4. Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. 5. Institute for Molecular Medicine I, Heinrich Heine University, University Hospital Düsseldorf , Düsseldorf, Germany. 6. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, and Technical University Dresden , Dresden, Germany. 7. Department of Medicine III, University Hospital Carl Gustav Carus, Technical University Dresden , Dresden, Germany. 8. Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 9. German Center for Diabetes Research, München-Neuherberg, Germany. 10. Translational Skin Cancer Research, University Duisburg-Essen, Essen, Germany. 11. German Cancer Research Center (DKFZ), Heidelberg, Germany. 12. Molecular Proteomics Laboratory, Biomedical Research Center (BMFZ), Heinrich Heine University, Medical Faculty, Düsseldorf, Germany. 13. Department of Pediatric Neurosurgery, Necker Hospital, Paris Descartes University, Paris, France. 14. Institut Curie, PSL Research University, Université Paris Sud, Université Paris-Saclay, Orsay, France. 15. Department of Neurosurgery, Hospital Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, Portugal.
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.
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.
Authors: Gerold Untergasser; Michael Steurer; Martina Zimmermann; Martin Hermann; Johann Kern; Albert Amberger; Günther Gastl; Eberhard Gunsilius Journal: Int J Cancer Date: 2008-04-01 Impact factor: 7.396
Authors: Vijay Ramaswamy; Marc Remke; Eric Bouffet; Simon Bailey; Steven C Clifford; Francois Doz; Marcel Kool; Christelle Dufour; Gilles Vassal; Till Milde; Olaf Witt; Katja von Hoff; Torsten Pietsch; Paul A Northcott; Amar Gajjar; Giles W Robinson; Laetitia Padovani; Nicolas André; Maura Massimino; Barry Pizer; Roger Packer; Stefan Rutkowski; Stefan M Pfister; Michael D Taylor; Scott L Pomeroy Journal: Acta Neuropathol Date: 2016-04-04 Impact factor: 17.088
Authors: Michael D Taylor; Paul A Northcott; Andrey Korshunov; Marc Remke; Yoon-Jae Cho; Steven C Clifford; Charles G Eberhart; D Williams Parsons; Stefan Rutkowski; Amar Gajjar; David W Ellison; Peter Lichter; Richard J Gilbertson; Scott L Pomeroy; Marcel Kool; Stefan M Pfister Journal: Acta Neuropathol Date: 2011-12-02 Impact factor: 17.088