Single-Cell Transcriptomics Uncovers Glial Progenitor Diversity and Cell Fate Determinants during Development and Gliomagenesis

Weng, Qinjie; Wang, Jincheng; Wang, Jiajia; He, Danyang; Cheng, Zuolin; Zhang, Feng; Verma, Ravinder; Xu, Lei; Dong, Xinran; Liao, Yunfei; He, Xuelian; Potter, Andrew; Zhang, Liguo; Zhao, Chuntao; Xin, Mei; Zhou, Qian; Aronow, Bruce J.; Blackshear, Perry J.; Rich, Jeremy; He, Qiaojun; Zhou, Wenhao; Suvà, Mario L.; Waclaw, Ronald R.; Potter, S. Steven; Yu, Guoqiang; Lü, Qing

doi:10.1016/j.stem.2019.03.006

Cited by 166 publications

(174 citation statements)

References 51 publications

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“…Here we show that classical glioma TME components such as microglia/macrophages, astrocytes and OPCs are present in xenografted tumors, indicating that tumor cell interactions with the TME remain active in PDOX. Of note, we observe a similar transcriptomic shift in tumor-associated microglia/macrophages as described in GBM patients 59,91 . It remains to be determined to what extent these models will be amenable to immunotherapeutic studies targeting tumor-associated microglia/macrophages.…”

Section: Discussionsupporting

confidence: 82%

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Golebiewska

Hau

Oudin

et al. 2020

Preprint

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Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies.

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Section: Discussionsupporting

confidence: 82%

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Golebiewska

Hau

Oudin

et al. 2020

Preprint

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“…Human brain cancer is a devastating disease, with a median survival of less than two years for glioblastoma. Recent work using single-cell RNA-sequencing to determine the cellular composition of glioblastoma has suggested that these tumors reflect a reversion to an embryonic cell state resembling neural progenitors, OPCs and/or immature astrocytes 24,43,44 . To unambiguously test this hypothesis, we compared human brain tumor data -comprising five glioblastoma samples and one anaplastic astrocytoma 45 -with a reference cell type catalog constructed by merging the developmental cell atlas of this paper with our previous adolescent brain cell atlas 22 (Methods and Extended Data Figure 9).…”

Section: • Metadatamentioning

confidence: 99%

Molecular architecture of the developing mouse brain

Manno

Siletti

Furlan

et al. 2020

Preprint

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The mammalian brain develops through a complex interplay of spatial cues generated by diffusible morphogens, cell-cell interactions, and intrinsic genetic programs that result in the generation of likely more than a thousand distinct cell types. Therefore, a complete understanding of mammalian brain development requires systematic mapping of cell states covering the entire relevant spatiotemporal range. Here we report a comprehensive single-cell transcriptome atlas of mouse brain development spanning from gastrulation to birth. We identified almost a thousand distinct cellular states, including the initial emergence of the neuroepithelium, a rich set of region-specific secondary organizers and a complete developmental program for the functional elements of the brain and its enclosing membranes. We used the atlas to directly test the hypothesis that human glioblastoma reflects a return to a developmental cell state. In agreement, most aneuploid tumor cells matched embryonic rather than adult types, while karyotypically normal cells predominantly matched adult immune cell types.

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“…105 Several groups consistently reported that the OPC-like cellular population constitutes the actively proliferating fraction of glioma cells. 74,97,105,106 In addition, it will be interesting to elucidate if cellular subpopulations differ in the extent of therapy resistance and network integration.…”

Section: Neurodevelopmental Origins Of Gliomasmentioning

confidence: 99%

Neuronal signatures in cancer

Jung

Alfonso

Monyer

et al. 2020

Intl Journal of Cancer

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Despite advances in the treatment of solid tumors, the prognosis of patients with many cancers remains poor, particularly of those with primary and metastatic brain tumors. In the last years, "Cancer Neuroscience" emerged as novel field of research at the crossroads of oncology and classical neuroscience. In primary brain tumors, including glioblastoma (GB), communicating networks that render tumor cells resistant against cytotoxic therapies were identified. To build these networks, GB cells extend neurite-like protrusions called tumor microtubes (TMs). Synapses on TMs allow tumor cells to retrieve neuronal input that fosters growth. Single cell sequencing further revealed that primary brain tumors recapitulate many steps of neurodevelopment. Interestingly, neuronal characteristics, including the ability to extend neurite-like protrusions, neuronal gene expression signatures and interactions with neurons, have now been found not only in brain and neuroendocrine tumors but also in some cancers of epithelial origin. In this review, we will provide an overview about neurite-like protrusions as well as neurodevelopmental origins, hierarchies and gene expression signatures in cancer. We will also discuss how "Cancer Neuroscience" might provide a framework for the development of novel therapies.

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Single-Cell Transcriptomics Uncovers Glial Progenitor Diversity and Cell Fate Determinants during Development and Gliomagenesis

Cited by 166 publications

References 51 publications

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Molecular architecture of the developing mouse brain

Neuronal signatures in cancer

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