Spatio-temporal transcriptomics of chromothriptic SHH-medulloblastoma identifies multiple genetic clones that resist treatment and drive relapse

Ilia Kats, Milena Simovic-Lorenz, Hannah Sophia Schreiber, Pooja Sant, Jan-Philipp Mallm, Verena Körber, Albert Li, Pravin Velmurugan, Sophie Heuer, Luisa Kües, Frauke Devens, Martin Sill, Manfred Jugold, Mahmoud Moustafa, Amir Abdollahi, Frank Winkler, Andrey Korshunov, Stefan M. Pfister, Oliver Stegle () and Aurélie Ernst ()
Additional contact information
Ilia Kats: German Cancer Research Centre (DKFZ)
Milena Simovic-Lorenz: German Cancer Research Centre (DKFZ)
Hannah Sophia Schreiber: German Cancer Research Centre (DKFZ)
Pooja Sant: German Cancer Research Center (DKFZ)
Jan-Philipp Mallm: German Cancer Research Center (DKFZ)
Verena Körber: University of Oxford
Albert Li: German Cancer Research Centre (DKFZ)
Pravin Velmurugan: German Cancer Research Centre (DKFZ)
Sophie Heuer: German Cancer Consortium (DKTK)
Luisa Kües: German Cancer Consortium (DKTK)
Frauke Devens: German Cancer Research Centre (DKFZ)
Martin Sill: German Cancer Consortium (DKTK)
Manfred Jugold: German Cancer Research Center (DKFZ)
Mahmoud Moustafa: German Cancer Consortium (DKTK)
Amir Abdollahi: German Cancer Consortium (DKTK)
Frank Winkler: German Cancer Consortium (DKTK)
Andrey Korshunov: German Cancer Consortium (DKTK)
Stefan M. Pfister: German Cancer Consortium (DKTK)
Oliver Stegle: German Cancer Research Centre (DKFZ)
Aurélie Ernst: German Cancer Research Centre (DKFZ)

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54709-w

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