Single-cell chromatin accessibility profiling of glioblastoma identifies an Invasive cancer stem cell population associated with lower survival
- University Health Network, Canada
- The Hospital for Sick Children, Canada
- Hospital for Sick Children, Canada
- University of Calgary, Canada
- Pharmaceutical Sciences, Canada
- University of Toronto, Canada
Abstract
Chromatin accessibility discriminates stem from mature cell populations, enabling the identification of primitive stem-like cells in primary tumors, such as Glioblastoma (GBM) where self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic intervention. We show, using single-cell chromatin accessibility, that primary human GBMs harbor a heterogeneous self-renewing population whose diversity is captured in patient-derived glioblastoma stem cells (GSCs). In depth characterization of chromatin accessibility in GSCs identifies three GSC states: Reactive, Constructive, and Invasive, each governed by uniquely essential transcription factors and present within GBMs in varying proportions. Orthotopic xenografts reveal that GSC states associate with survival, and identify an invasive GSC signature predictive of low patient survival, in line with the higher invasive properties of Invasive state GSCs compared to Reactive and Constructive GSCs as shown by in vitro and in vivo assays. Our chromatin-driven characterization of GSC states improves prognostic precision and identifies dependencies to guide combination therapies.
Data availability
The GSCs are available upon reasonable request from PBD and SW. The GSC ATAC-seq and DNA methylation data have been deposited at GEO (GSE109399). The scATAC-seq data has been deposited at GEO (GSE139136). RNA-seq data are available at EGA (EGAS00001003070).
-
Epigenetic characterization of glioblastoma stem cellsNCBI Gene Expression Omnibus, GSE109399.
-
Single-cell ATAC-Seq of Adult GBMNCBI Gene Expression Omnibus, GSE139136.
Article and author information
Author details
Funding
CIHR (TGH-158221)
- Stephane Angers
- Peter B Dirks
- Mathieu Lupien
SU2C canada (SU2C-AACR-DT-19-15)
- Michael D Taylor
- Sam Weiss
- Peter B Dirks
- Mathieu Lupien
CIHR (MFE 338954)
- Paul Guilhamon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal procedures were performed according to and approved by the Animal Care Committee of the Hospital for Sick Children or the University of Calgary. All attempts are made to minimize the handling time during surgery and treatment so as not to unduly stress the animals. Animals are observed daily after surgery to ensure there are no unexpected complications
Human subjects: All tissue samples were obtained following informed consent from patients, and all experimental procedures were performed in accordance with the Research Ethics Board at The Hospital for Sick Children (Toronto, Canada), the University of Calgary Ethics Review Board, and the Health Research Ethics Board of Alberta - Cancer Committee (HREBA). Approval to pathological data was obtained from the respective institutional review boards.
Reviewing Editor
- Lynne-Marie Postovit, University of Alberta, Canada
Version history
- Received: October 17, 2020
- Accepted: January 8, 2021
- Accepted Manuscript published: January 11, 2021 (version 1)
- Version of Record published: January 29, 2021 (version 2)
Copyright
© 2021, Guilhamon et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 7,703
- Page views
-
- 959
- Downloads
-
- 36
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Single-cell chromatin accessibility profiling of glioblastoma identifies an Invasive cancer stem cell population associated with lower survival
eLife 10:e64090.
https://doi.org/10.7554/eLife.64090
Further reading
-
- Cancer Biology
- Computational and Systems Biology
Pancreatic cancer is one of the deadliest cancer types with poor treatment options. Better detection of early symptoms and relevant disease correlations could improve pancreatic cancer prognosis. In this retrospective study, we used symptom and disease codes (ICD-10) from the Danish National Patient Registry (NPR) encompassing 6.9 million patients from 1994 to 2018,, of whom 23,592 were diagnosed with pancreatic cancer. The Danish cancer registry included 18,523 of these patients. To complement and compare the registry diagnosis codes with deeper clinical data, we used a text mining approach to extract symptoms from free text clinical notes in electronic health records (3078 pancreatic cancer patients and 30,780 controls). We used both data sources to generate and compare symptom disease trajectories to uncover temporal patterns of symptoms prior to pancreatic cancer diagnosis for the same patients. We show that the text mining of the clinical notes was able to complement the registry-based symptoms by capturing more symptoms prior to pancreatic cancer diagnosis. For example, ‘Blood pressure reading without diagnosis’, ‘Abnormalities of heartbeat’, and ‘Intestinal obstruction’ were not found for the registry-based analysis. Chaining symptoms together in trajectories identified two groups of patients with lower median survival (<90 days) following the trajectories ‘Cough→Jaundice→Intestinal obstruction’ and ‘Pain→Jaundice→Abnormal results of function studies’. These results provide a comprehensive comparison of the two types of pancreatic cancer symptom trajectories, which in combination can leverage the full potential of the health data and ultimately provide a fuller picture for detection of early risk factors for pancreatic cancer.
-
- Cancer Biology
Cancer stem cells (CSCs) undergo epithelial-mesenchymal transition (EMT) to drive metastatic dissemination in experimental cancer models. However, tumour cells undergoing EMT have not been observed disseminating into the tissue surrounding human tumour specimens, leaving the relevance to human cancer uncertain. We have previously identified both EpCAM and CD24 as CSC markers that, alongside the mesenchymal marker Vimentin, identify EMT CSCs in human oral cancer cell lines. This afforded the opportunity to investigate whether the combination of these three markers can identify disseminating EMT CSCs in actual human tumours. Examining disseminating tumour cells in over 12,000 imaging fields from 74 human oral tumours, we see a significant enrichment of EpCAM, CD24 and Vimentin co-stained cells disseminating beyond the tumour body in metastatic specimens. Through training an artificial neural network, these predict metastasis with high accuracy (cross-validated accuracy of 87-89%). In this study, we have observed single disseminating EMT CSCs in human oral cancer specimens, and these are highly predictive of metastatic disease.
