Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia.
The University of Queensland Frazer Institute, Translational Research Institute, Woolloongabba, QLD, 4102, Australia.
Genome Med. 2023 May 1;15(1):29. doi: 10.1186/s13073-023-01185-4.
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.
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.
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.
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.
髓母细胞瘤（MB）是一种小脑恶性肿瘤，可以根据基因表达和基因组特征分为四个主要亚组。单细胞转录组研究已经定义了每个 MB 亚组的细胞状态；然而，这些不同细胞状态的空间组织以及这如何影响对治疗的反应仍有待确定。
在这里，我们使用空间分辨转录组学来定义 sonic hedgehog (SHH) 患者来源的 MB 模型中的细胞多样性，并表明特定于转录状态或空间位置的细胞对于 CDK4/6 抑制剂 Palbociclib 的治疗反应至关重要。我们将空间基因表达与组织学注释以及来自 MB 的单细胞基因表达数据进行整合，开发了一种分析策略，以在人源和鼠源细胞的混合系统内以及在完整脑肿瘤切片内的细胞界面上对细胞类型反应进行空间映射。
我们区分了肿瘤内和周围小脑组织中的肿瘤和非肿瘤细胞，并进一步细化了病理注释。我们发现 Palbociclib 具有区域性反应，在治疗的肿瘤中均减少了增殖并诱导了神经元分化。此外，我们以细胞分辨率解析了一个独特的肿瘤界面，在该界面中，肿瘤与邻近的小鼠脑组织接触，其中包含丰富的星形胶质细胞和小胶质细胞，尽管接受了 Palbociclib 治疗，但仍继续增殖。
我们的数据突出了使用空间转录组学来描述肿瘤对靶向治疗的反应的强大功能，并为 SHH MB 中 CDK4/6 抑制剂的反应和耐药性的分子和细胞基础提供了更深入的见解。
