Intratumoral heterogeneity of MYC drives medulloblastoma metastasis and angiogenesis
Publikation: Beitrag in Fachzeitschrift › Forschungsartikel › Beigetragen › Begutachtung
Beitragende
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.
Details
Originalsprache | Englisch |
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Seiten (von - bis) | 1509-1523 |
Seitenumfang | 15 |
Fachzeitschrift | Neuro-oncology |
Jahrgang | 24 |
Ausgabenummer | 9 |
Publikationsstatus | Veröffentlicht - 1 Sept. 2022 |
Peer-Review-Status | Ja |
Externe IDs
PubMedCentral | PMC9435486 |
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Scopus | 85132262362 |
ORCID | /0000-0002-6932-333X/work/148144957 |
Schlagworte
Ziele für nachhaltige Entwicklung
Schlagwörter
- Cerebellar Neoplasms/pathology, Humans, In Situ Hybridization, Fluorescence, Medulloblastoma/pathology, Prognosis, Proto-Oncogene Proteins c-myc/genetics