Journal Article

DKFZ-2024-02459

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Spatio-temporal transcriptomics of chromothriptic SHH-medulloblastoma identifies multiple genetic clones that resist treatment and drive relapse.

Kats, I. (First author)DKFZ* ; Simovic-Lorenz, M. (First author)DKFZ* ; Schreiber, H. (First author)DKFZ* ; Sant, P.DKFZ* ; Mallm, J.-P.DKFZ* ; Körber, V. ; Li, A.DKFZ* ; Velmurugan, P.DKFZ* ; Heuer, S.DKFZ* ; Kües, L.DKFZ* ; Devens, F.DKFZ* ; Sill, M.DKFZ* ; Jugold, M.DKFZ* ; Moustafa, M.DKFZ* ; Abdollahi, A.DKFZ* ; Winkler, F.DKFZ* ; Korshunov, A.DKFZ* ; Pfister, S.DKFZ* ; Stegle, O.DKFZ* ; Ernst, A. (Last author)DKFZ*

2024
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-024-54709-w

Abstract: Paediatric medulloblastomas with chromothripsis are characterised by high genomic instability and are among the tumours with the worst prognosis. However, the molecular makeup and the determinants of the aggressiveness of chromothriptic medulloblastoma are not well understood. Here, we apply spatial transcriptomics to profile a cohort of 13 chromothriptic and non-chromothriptic medulloblastomas from the same molecular subgroup. Our data reveal a higher extent of spatial intra-tumour heterogeneity in chromothriptic medulloblastomas compared to non-chromothripictic tumours, which is associated with increased proliferation and stemness, but lower immune infiltration and differentiation. Spatial mapping of genetic subclones of the same tumour identify a regionally distinct architecture and clone-specific phenotypic features, with distinct degrees of differentiation, proliferation and immune infiltration between clones. We conduct temporal profiling of 11 samples from patient-derived xenografts from a patient with chromothriptic medulloblastoma, covering the transition from the minimal residual disease stage to treatment-resistant regrown tumours. In chromothriptic medulloblastoma, an ecosystem of cells from multiple genetic clones resist treatment and lead to relapse. Finally, we identify tumour microtubes in chromothriptic medulloblastoma, calling for exploration of cell network communication as a putative target.

Keyword(s): Medulloblastoma: genetics (MeSH) ; Medulloblastoma: pathology (MeSH) ; Medulloblastoma: metabolism (MeSH) ; Humans (MeSH) ; Cerebellar Neoplasms: genetics (MeSH) ; Cerebellar Neoplasms: pathology (MeSH) ; Cerebellar Neoplasms: metabolism (MeSH) ; Animals (MeSH) ; Transcriptome (MeSH) ; Hedgehog Proteins: metabolism (MeSH) ; Hedgehog Proteins: genetics (MeSH) ; Neoplasm Recurrence, Local: genetics (MeSH) ; Chromothripsis (MeSH) ; Child (MeSH) ; Mice (MeSH) ; Male (MeSH) ; Female (MeSH) ; Child, Preschool (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Cell Proliferation: genetics (MeSH) ; Gene Expression Profiling (MeSH) ; Genomic Instability (MeSH) ; Clone Cells (MeSH) ; Hedgehog Proteins ; SHH protein, human

Note: #EA:B260#LA:B420#LA:B420#

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Contributing Institute(s):

1. B260 Bioinformatik der Genomik und Systemgenetik (B260)
2. Genominstabilität in Tumoren (B420)
3. scOpen Lab (W192)
4. KKE Neuroonkologie (B320)
5. B062 Pädiatrische Neuroonkologie (B062)
6. Core Facility-Kleintierbildgebung (W240)
7. E210 KKE Translationale Radioonkologie (E210)
8. KKE Neuropathologie (B300)
9. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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