Unveiling spatial heterogeneity in medulloblastoma: a multi-omics analysis of cellular state and geographical organization.

in Neuro-oncology by Jiankang Li, Hailong Liu, Ziwei Wang, Jiao Zhang, Xuan Chen, Craig Daniels, Xiaochong Wu, Olivier Saulnier, Hiromichi Suzuki, Pasqualino De Antonellis, Alexandra Rasnitsyn, Winnie Ong, Evan Y Wang, Liam D Hendrikse, Yu Su, Yu Tian, Dongming Han, Ruohan Wang, Jialin Mo, Fei Liu, Kaiwen Deng, Dongyang Wang, Zhaoyang Feng, Yifei Jiang, Yanong Li, Yuting Ma, Zijia Liu, Meiyu Li, Peiyi Tian, Yanfeng Shi, Yong Jiang, Tao Yang, Shouwei Li, Jianfeng Liang, Jingchuan Wu, Ying Wang, Wanjing Zou, Yina Jiang, Lusheng Wang, Fang Chen, Xin Jin, Shuaicheng Li, Xiaoguang Qiu, Chunde Li, Ya Gao, Yujie Tang, Michael D Taylor, Tao Jiang

TLDR

  • The study analyzed single-nucleus and spatial transcriptomes, chromatin accessibility, and chromosomal variations to understand the spatial organization of medulloblastoma cell populations.
  • Three main malignant cell populations were identified, correlated to clinical outcomes, and were distributed in stem-like and mature regions.
  • The findings highlight the importance of considering spatial heterogeneity in MB cell populations for developing novel therapeutic strategies.

Abstract

Despite numerous studies on medulloblastoma (MB) cell heterogeneity, the spatial characteristics of cellular states remain unclear. We analyze single-nucleus and spatial transcriptomes and chromatin accessibility from human MB spanning four subgroups, to identify malignant cell populations and describe the spatial evolutionary trajectories. The spatial CNVs patterns and niches were analyzed to investigate the cellular interactions. Three main malignant cell populations were identified, including progenitor-like, cycling and differentiated populations. Gene signatures of cell populations strongly correlate to clinical outcomes. These tumor cell populations are geographically organized as stem-like and mature regions, highlighting their spatially heterogeneous nature. Progenitor-like and cycling cells are mainly concentrated in stem-like regions, whereas various differentiated populations are primarily distributed in mature regions. By analyzing chromosomal alterations, we find that stem-like region typically harbors a single pattern of CNVs, reflecting high originality and uniformity, which is in stark contrast to mature region exhibiting multiple patterns with a broader range of biological functions. Projecting cellular state program onto spatial sections fully illustrates the evolution from stem-like region to various functional zones in mature region, which is correlated to microenvironmental components along the paths to maintain stemness or promote differentiation. Conclusions. This multi-omics database comprehensively facilitates the understanding of MB spatial evolutionary organization.

Overview

  • The study examines medulloblastoma (MB) cell heterogeneity by analyzing single-nucleus and spatial transcriptomes, chromatin accessibility, and chromosomal variations.
  • The researchers identified three main malignant cell populations: progenitor-like, cycling, and differentiated populations, which are spatially organized as stem-like and mature regions.
  • The study aimed to describe the spatial evolutionary trajectories and cellular interactions in MB, and to explore the correlation between cellular populations and clinical outcomes.

Comparative Analysis & Findings

  • The analysis revealed that stem-like regions harbor a single pattern of chromosomal variations, reflecting high originality and uniformity, whereas mature regions exhibit multiple patterns with a broader range of biological functions.
  • Progenitor-like and cycling cells are mainly concentrated in stem-like regions, whereas various differentiated populations are primarily distributed in mature regions.
  • Gene signatures of cell populations strongly correlate to clinical outcomes, indicating the importance of understanding the spatial organization of MB cell populations for treatment and prognosis.

Implications and Future Directions

  • The study highlights the significance of considering the spatial organization of MB cell populations in understanding the disease, particularly in the development of novel therapeutic strategies.
  • Future research should investigate the impact of spatially heterogeneous MB cell populations on treatment response and resistance.
  • The multi-omics database generated by this study can serve as a resource for further research, providing insights into the evolutionary trajectories of MB and the interactions between cellular populations.
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