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

Research

Dharmesh D. Bhuva¹  Thomas Robertson²  Kahli Jones³  Onkar Mulay³  Tuan Vo³  Guiyan Ni³  Quan Nguyen³  Brad Balderson³  Joanna Crawford³  Laura A. Genovesi⁴  Shaun Walters⁵  Brandon J. Wainwright⁶  Marija Kojic⁶  Elissa Tolson⁶  Amanda Millar⁶  Matthew Singleton⁶  Melissa J. Davis⁷ 

[1] Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, 3052, Parkville, VIC, Australia;Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, 3010, Melbourne, VIC, Australia;Faculty of Medicine, South Australian Immunogenomics Cancer Institute, The University of Adelaide, 5000, Adelaide, SA, Australia;Department of Pathology, Royal Brisbane and Women’s Hospital, University of Queensland, 4029, Brisbane, QLD, Australia;Institute for Molecular Bioscience, The University of Queensland, 4072, St Lucia, QLD, Australia;Institute for Molecular Bioscience, The University of Queensland, 4072, St Lucia, QLD, Australia;The University of Queensland Frazer Institute, Translational Research Institute, 4102, Woolloongabba, QLD, Australia;School of Biomedical Sciences, The University of Queensland, 4072, St Lucia, QLD, Australia;The University of Queensland Frazer Institute, Translational Research Institute, 4102, Woolloongabba, QLD, Australia;The University of Queensland Frazer Institute, Translational Research Institute, 4102, Woolloongabba, QLD, Australia;Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, 3052, Parkville, VIC, Australia;Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, 3010, Melbourne, VIC, Australia;Faculty of Medicine, South Australian Immunogenomics Cancer Institute, The University of Adelaide, 5000, Adelaide, SA, Australia;Department of Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, 3010, Melbourne, VIC, Australia;

关键词: Medulloblastoma;    Spatial transcriptomics;    Visium;    Palbociclib;    CDK4/6 inhibitor;    Neuron differentiation;    Relapse;   

DOI  :  10.1186/s13073-023-01185-4

 received in 2022-07-06, accepted in 2023-04-20,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMedulloblastoma (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.MethodsHere, 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.ResultsWe 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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