Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse

Zhang, Liguo; He, Xuelian; Liu, Xuezhao; Zhang, Feng; Huang, Lei; Potter, Andrew; Xu, Lei; Zhou, Wenhao; Zheng, Tao; Luo, Zaili; Berry, Kalen; Pribnow, Allison; Smith, Sally J.; Fuller, Christine; Jones, Blaise V.; Fouladi, Maryam; Drissi, Rachid; Yang, Zeng-jie; Gustafson, W. Clay; Remke, Marc; Pomeroy, Scott L.; Girard, Emily J.; Olson, James M.; Morrissy, A. Sorana; Vladoiu, Maria C.; Zhang, Jiao; Tian, Weidong; Xin, Mei; Taylor, Michael D.; Potter, S. Steven; Roussel, Martine F.; Weiss, William A.; Lü, Qing

doi:10.1016/j.ccell.2019.07.009

Cited by 109 publications

(112 citation statements)

References 73 publications

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“…Actually, rescue from hypoxia has been described to require the expression of olig2, essential for functional myelination [69]. It is thus plausible to assume that the characteristic expression of olig2 by stem cell like progenitors giving rise to MB [70] is related to the consequences of this vicious cycle.…”

Section: Discussionmentioning

confidence: 99%

Determination of a Tumor-Promoting Microenvironment in Recurrent Medulloblastoma: A Multi-Omics Study of Cerebrospinal Fluid

Reichl

Niederstaetter

Boegl

et al. 2020

Cancers

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Molecular classification of medulloblastoma (MB) is well-established and reflects the cell origin and biological properties of tumor cells. However, limited data is available regarding the MB tumor microenvironment. Here, we present a mass spectrometry-based multi-omics pilot study of cerebrospinal fluid (CSF) from recurrent MB patients. A group of age-matched patients without a neoplastic disease was used as control cohort. Proteome profiling identified characteristic tumor markers, including FSTL5, ART3, and FMOD, and revealed a strong prevalence of anti-inflammatory and tumor-promoting proteins characteristic for alternatively polarized myeloid cells in MB samples. The up-regulation of ADAMTS1, GAP43 and GPR37 indicated hypoxic conditions in the CSF of MB patients. This notion was independently supported by metabolomics, demonstrating the up-regulation of tryptophan, methionine, serine and lysine, which have all been described to be induced upon hypoxia in CSF. While cyclooxygenase products were hardly detectable, the epoxygenase product and beta-oxidation promoting lipid hormone 12,13-DiHOME was found to be strongly up-regulated. Taken together, the data suggest a vicious cycle driven by autophagy, the formation of 12,13-DiHOME and increased beta-oxidation, thus promoting a metabolic shift supporting the formation of drug resistance and stem cell properties of MB cells. In conclusion, the different omics-techniques clearly synergized and mutually supported a novel model for a specific pathomechanism.

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Section: Discussionmentioning

confidence: 99%

Determination of a Tumor-Promoting Microenvironment in Recurrent Medulloblastoma: A Multi-Omics Study of Cerebrospinal Fluid

Reichl

Niederstaetter

Boegl

et al. 2020

Cancers

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“…Although MBs are thought to originate from primitive and undeveloped cells in the brain, the cell of origin for MB subgroups remains controversial. Most recently, three single-cell RNA sequencing (scRNA-seq) studies have provided a clearer picture of MB putative subtype-specific origins, highlighting the molecular and cellular diversity of MB across all subgroups, with the potential insights into understanding of tumor development and treatment response [17][18][19].…”

Section: Cell Of Origins In Mb Subgroupsmentioning

confidence: 99%

“…Furthermore, genetically engineered mouse model studies demonstrated that SHH MBs arise from cerebellar granule neuron progenitors (GNPs) [62,63]. By single-cell transcriptomics of SHH mouse models, OLIG2 + glial lineage progenitors were identified to play a pivotal role in tumor initiation, therapy-resistance and recurrence [19]. Interestingly, SHH MBs in infants (≤3 years old) and adults (≥16 years old) are thought to originate from different GNP populations.…”

Section: Cell Of Origins In Mb Subgroupsmentioning

confidence: 99%

“…Recently, single-cell RNA sequencing (scRNA-seq) based studies provided new insights on molecular and cellular heterogeneity, which underlie the divergent biology and clinical behavior in MB [17][18][19]. This review is meant to explore the intratumoral and intertumoral heterogeneity and diversity that characterize MB, and how the differences between the subgroups could potentially contribute to the treatment and/or prognosis of affected patients.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Heterogeneity and Cellular Diversity: Implications for Precision Treatment in Medulloblastoma

Zou

Poore

Broniscer

et al. 2020

Cancers

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Medulloblastoma, the most common pediatric malignant brain tumor, continues to have a high rate of morbidity and mortality in childhood. Recent advances in cancer genomics, single-cell sequencing, and sophisticated tumor models have revolutionized the characterization and stratification of medulloblastoma. In this review, we discuss heterogeneity associated with four major subgroups of medulloblastoma (WNT, SHH, Group 3, and Group 4) on the molecular and cellular levels, including histological features, genetic and epigenetic alterations, proteomic landscape, cell-of-origin, tumor microenvironment, and therapeutic approaches. The intratumoral molecular heterogeneity and intertumoral cellular diversity clearly underlie the divergent biology and clinical behavior of these lesions and highlight the future role of precision treatment in this devastating brain tumor in children.

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“…In glioblastoma, OLIG2 and RUNX2 TFs (among many other TFs) have been shown to robustly segregate two distinct cell states that have differential response to drug therapy; and suggest that these cells may contribute uniquely to therapeutic resistance [16]. Furthermore, OLIG2 has been shown to mark tumour propagating cells in both glioma and medulloblastoma, and associated with tumorigenesis and relapse [36,44]. In another instance, coordinated activity of core TFs: POU3F2, SOX2, SALL2 and OLIG2 are capable of reprogramming differentiated glioblastoma cells and restoring their tumourigenic capacity [45].…”

Section: Reverse‐engineering Enhancers To Characterize Transcription mentioning

confidence: 99%

Invited Review: The role and contribution of transcriptional enhancers in brain cancer

Arabzade

Stuckert

Bertrand

et al. 2020

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 48-56 The role and contribution of transcriptional enhancers in brain cancer Genetic alterations identified across several paediatric and adult brain tumours reveal recurrent disruption of active chromatin landscapes and dysregulation of transcriptional programmes. Noncoding elements, specifically enhancers, are central to these mechanisms, and are influenced by developmental and neural gene regulatory signatures. Epigenomic and transcriptomic methods and techniques have facilitated detection of active enhancers, and characterization of brain tumours integrated with genomic structural information. These datasets have provided new insights into the mechanisms of transcriptional control that are profoundly altered in childhood and adult brain cancer; offering new ideas and molecular targets for therapeutic intervention. This review summarizes recent advances in our understanding of active transcriptional programmes of brain cancer, their impact on tumour development, and research areas for further exploration.

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Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse

Cited by 109 publications

References 73 publications

Determination of a Tumor-Promoting Microenvironment in Recurrent Medulloblastoma: A Multi-Omics Study of Cerebrospinal Fluid

Determination of a Tumor-Promoting Microenvironment in Recurrent Medulloblastoma: A Multi-Omics Study of Cerebrospinal Fluid

Molecular Heterogeneity and Cellular Diversity: Implications for Precision Treatment in Medulloblastoma

Invited Review: The role and contribution of transcriptional enhancers in brain cancer

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