TY  - JOUR
AU  - Kats, Ilia
AU  - Simovic-Lorenz, Milena
AU  - Schreiber, Hannah
AU  - Sant, Pooja
AU  - Mallm, Jan-Philipp
AU  - Körber, Verena
AU  - Li, Albert
AU  - Velmurugan, Pravin
AU  - Heuer, Sophie
AU  - Kües, Luisa
AU  - Devens, Frauke
AU  - Sill, Martin
AU  - Jugold, Manfred
AU  - Moustafa, Mahmoud
AU  - Abdollahi, Amir
AU  - Winkler, Frank
AU  - Korshunov, Andrey
AU  - Pfister, Stefan
AU  - Stegle, Oliver
AU  - Ernst, Aurélie
TI  - Spatio-temporal transcriptomics of chromothriptic SHH-medulloblastoma identifies multiple genetic clones that resist treatment and drive relapse.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2024-02459
SP  - 10370
PY  - 2024
N1  - #EA:B260#LA:B420#LA:B420#
AB  - 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.
KW  - Medulloblastoma: genetics
KW  - Medulloblastoma: pathology
KW  - Medulloblastoma: metabolism
KW  - Humans
KW  - Cerebellar Neoplasms: genetics
KW  - Cerebellar Neoplasms: pathology
KW  - Cerebellar Neoplasms: metabolism
KW  - Animals
KW  - Transcriptome
KW  - Hedgehog Proteins: metabolism
KW  - Hedgehog Proteins: genetics
KW  - Neoplasm Recurrence, Local: genetics
KW  - Chromothripsis
KW  - Child
KW  - Mice
KW  - Male
KW  - Female
KW  - Child, Preschool
KW  - Gene Expression Regulation, Neoplastic
KW  - Cell Proliferation: genetics
KW  - Gene Expression Profiling
KW  - Genomic Instability
KW  - Clone Cells
KW  - Hedgehog Proteins (NLM Chemicals)
KW  - SHH protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39609432
C2  - pmc:PMC11604656
DO  - DOI:10.1038/s41467-024-54709-w
UR  - https://inrepo02.dkfz.de/record/294744
ER  -