Spatial transcriptomic analysis of Sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition
Abstract Background Medulloblastoma (MB) is a malignant tumour of the cerebellum which can be classified into four major subgroups based on gene expression and genomic features. Single-cell transcriptome studies have defined the cellular states underlying each MB subgroup; however, the spatial organ...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-023-01185-4 |
| _version_ | 1797822740400439296 |
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| author | Tuan Vo Brad Balderson Kahli Jones Guiyan Ni Joanna Crawford Amanda Millar Elissa Tolson Matthew Singleton Marija Kojic Thomas Robertson Shaun Walters Onkar Mulay Dharmesh D. Bhuva Melissa J. Davis Brandon J. Wainwright Quan Nguyen Laura A. Genovesi |
| author_facet | Tuan Vo Brad Balderson Kahli Jones Guiyan Ni Joanna Crawford Amanda Millar Elissa Tolson Matthew Singleton Marija Kojic Thomas Robertson Shaun Walters Onkar Mulay Dharmesh D. Bhuva Melissa J. Davis Brandon J. Wainwright Quan Nguyen Laura A. Genovesi |
| author_sort | Tuan Vo |
| collection | DOAJ |
| description | Abstract Background Medulloblastoma (MB) is a malignant tumour of the cerebellum which can be classified into four major subgroups based on gene expression and genomic features. Single-cell transcriptome studies have defined the cellular states underlying each MB subgroup; however, the spatial organisation of these diverse cell states and how this impacts response to therapy remains to be determined. Methods Here, we used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of MB and show that cells specific to a transcriptional state or spatial location are pivotal for CDK4/6 inhibitor, Palbociclib, treatment response. We integrated spatial gene expression with histological annotation and single-cell gene expression data from MB, developing an analysis strategy to spatially map cell type responses within the hybrid system of human and mouse cells and their interface within an intact brain tumour section. Results We distinguish neoplastic and non-neoplastic cells within tumours and from the surrounding cerebellar tissue, further refining pathological annotation. We identify a regional response to Palbociclib, with reduced proliferation and induced neuronal differentiation in both treated tumours. Additionally, we resolve at a cellular resolution a distinct tumour interface where the tumour contacts neighbouring mouse brain tissue consisting of abundant astrocytes and microglia and continues to proliferate despite Palbociclib treatment. Conclusions Our data highlight the power of using spatial transcriptomics to characterise the response of a tumour to a targeted therapy and provide further insights into the molecular and cellular basis underlying the response and resistance to CDK4/6 inhibitors in SHH MB. |
| first_indexed | 2024-03-13T10:13:38Z |
| format | Article |
| id | doaj.art-7b01e6e8430f4272932f8e0c58f61003 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-03-13T10:13:38Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-7b01e6e8430f4272932f8e0c58f610032023-05-21T11:22:26ZengBMCGenome Medicine1756-994X2023-05-0115112810.1186/s13073-023-01185-4Spatial transcriptomic analysis of Sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibitionTuan Vo0Brad Balderson1Kahli Jones2Guiyan Ni3Joanna Crawford4Amanda Millar5Elissa Tolson6Matthew Singleton7Marija Kojic8Thomas Robertson9Shaun Walters10Onkar Mulay11Dharmesh D. Bhuva12Melissa J. Davis13Brandon J. Wainwright14Quan Nguyen15Laura A. Genovesi16Institute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandThe University of Queensland Frazer Institute, Translational Research InstituteThe University of Queensland Frazer Institute, Translational Research InstituteThe University of Queensland Frazer Institute, Translational Research InstituteThe University of Queensland Frazer Institute, Translational Research InstituteDepartment of Pathology, Royal Brisbane and Women’s Hospital, University of QueenslandSchool of Biomedical Sciences, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandBioinformatics Division, The Walter and Eliza Hall Institute of Medical ResearchThe University of Queensland Frazer Institute, Translational Research InstituteThe University of Queensland Frazer Institute, Translational Research InstituteInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandAbstract Background Medulloblastoma (MB) is a malignant tumour of the cerebellum which can be classified into four major subgroups based on gene expression and genomic features. Single-cell transcriptome studies have defined the cellular states underlying each MB subgroup; however, the spatial organisation of these diverse cell states and how this impacts response to therapy remains to be determined. Methods Here, we used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of MB and show that cells specific to a transcriptional state or spatial location are pivotal for CDK4/6 inhibitor, Palbociclib, treatment response. We integrated spatial gene expression with histological annotation and single-cell gene expression data from MB, developing an analysis strategy to spatially map cell type responses within the hybrid system of human and mouse cells and their interface within an intact brain tumour section. Results We distinguish neoplastic and non-neoplastic cells within tumours and from the surrounding cerebellar tissue, further refining pathological annotation. We identify a regional response to Palbociclib, with reduced proliferation and induced neuronal differentiation in both treated tumours. Additionally, we resolve at a cellular resolution a distinct tumour interface where the tumour contacts neighbouring mouse brain tissue consisting of abundant astrocytes and microglia and continues to proliferate despite Palbociclib treatment. Conclusions Our data highlight the power of using spatial transcriptomics to characterise the response of a tumour to a targeted therapy and provide further insights into the molecular and cellular basis underlying the response and resistance to CDK4/6 inhibitors in SHH MB.https://doi.org/10.1186/s13073-023-01185-4MedulloblastomaSpatial transcriptomicsVisiumPalbociclibCDK4/6 inhibitorNeuron differentiation |
| spellingShingle | Tuan Vo Brad Balderson Kahli Jones Guiyan Ni Joanna Crawford Amanda Millar Elissa Tolson Matthew Singleton Marija Kojic Thomas Robertson Shaun Walters Onkar Mulay Dharmesh D. Bhuva Melissa J. Davis Brandon J. Wainwright Quan Nguyen Laura A. Genovesi Spatial transcriptomic analysis of Sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition Genome Medicine Medulloblastoma Spatial transcriptomics Visium Palbociclib CDK4/6 inhibitor Neuron differentiation |
| title | Spatial transcriptomic analysis of Sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition |
| title_full | Spatial transcriptomic analysis of Sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition |
| title_fullStr | Spatial transcriptomic analysis of Sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition |
| title_full_unstemmed | Spatial transcriptomic analysis of Sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition |
| title_short | Spatial transcriptomic analysis of Sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition |
| title_sort | spatial transcriptomic analysis of sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to cdk4 6 inhibition |
| topic | Medulloblastoma Spatial transcriptomics Visium Palbociclib CDK4/6 inhibitor Neuron differentiation |
| url | https://doi.org/10.1186/s13073-023-01185-4 |
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