Spatio-temporal transcriptomics of chromothriptic SHH-medulloblastoma identifies multiple genetic clones that resist treatment and drive relapse
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.
Authors
- Aurélie Ernst (ORCID: https://orcid.org/0000-0002-8082-3677)
- Milena Simović (ORCID: https://orcid.org/0000-0001-8835-6885)
- Frank Winkler (ORCID: https://orcid.org/0000-0003-4892-6104)
- Frauke Devens
- Manfred Jugold
- Pravin Velmurugan (ORCID: https://orcid.org/0009-0004-6241-1769)
- Andrey Korshunov (ORCID: https://orcid.org/0000-0002-5257-3623)
- Stefan M. Pfister (ORCID: https://orcid.org/0000-0002-5447-5322)
- Ilia Kats (ORCID: https://orcid.org/0000-0001-5220-5671)
- Pooja Sant (ORCID: https://orcid.org/0000-0001-9301-3211)
- Jan‐Philipp Mallm (ORCID: https://orcid.org/0000-0002-7059-4030)
- Hannah Sophia Schreiber (ORCID: https://orcid.org/0009-0009-0059-9133)
- Verena Körber (ORCID: https://orcid.org/0009-0005-3888-2648)
- Amir Abdollahi (ORCID: https://orcid.org/0000-0002-8016-5897)
- Mahmoud Moustafa (ORCID: https://orcid.org/0000-0002-9146-0808)
- Martin Sill (ORCID: https://orcid.org/0000-0001-7616-7665)
- Oliver Stegle (ORCID: https://orcid.org/0000-0002-8818-7193)
- Albert Li (ORCID: https://orcid.org/0000-0002-4590-3268)
- Sophie Heuer (ORCID: https://orcid.org/0000-0002-3373-5295)
- Luisa Kües
Institutions
- Suez Canal University (EG)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University of Oxford (GB)
- Heidelberger Institut für Radioonkologie (DE)
- MRC Weatherall Institute of Molecular Medicine (GB)
- National Center for Tumor Diseases (DE)
- Hopp Children's Cancer Center Heidelberg (DE)
- European Molecular Biology Laboratory (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1038/s41467-024-54709-w
- Citations
- 9
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 2.10