Charles P Couturier1, Javad Nadaf1,2,3, Zhaorong Li4, Salma Baig1, Gabriele Riva1, Phuong Le1, Daan J Kloosterman5, Jean Monlong2,3,6, Andriniaina Nkili Meyong1, Redouane Allache1, Theresa Degenhard1, Mariam Al-Rashid1, Marie-Christine Guiot7, Guillaume Bourque2,3, Jiannis Ragoussis2,3, Leila Akkari5, Francisco J Quintana4,8, Kevin Petrecca1. 1. Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada. 2. McGill University and Genome Québec Innovation Centre, Montreal, Quebec, Canada. 3. Department of Human Genetics, Canadian Centre for Computational Genomics, McGill University, Montreal, Quebec, Canada. 4. Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 5. Tumour Biology and Immunology Division, The Netherlands Cancer Institute, Oncode Institute, Amsterdam, The Netherlands. 6. UC Santa Cruz Genomics Institute, Santa Cruz, California, USA. 7. Department of Neuropathology, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada. 8. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Abstract
BACKGROUND: Glioblastoma is a treatment-resistant brain cancer. Its hierarchical cellular nature and its tumor microenvironment (TME) before, during, and after treatments remain unresolved. METHODS: Here, we used single-cell RNA sequencing to analyze new and recurrent glioblastoma and the nearby subventricular zone (SVZ). RESULTS: We found 4 glioblastoma neural lineages are present in new and recurrent glioblastoma with an enrichment of the cancer mesenchymal lineage, immune cells, and reactive astrocytes in early recurrences. Cancer lineages were hierarchically organized around cycling oligodendrocytic and astrocytic progenitors that are transcriptomically similar but distinct to SVZ neural stem cells (NSCs). Furthermore, NSCs from the SVZ of patients with glioblastoma harbored glioblastoma chromosomal anomalies. Lastly, mesenchymal cancer cells and TME reactive astrocytes shared similar gene signatures which were induced by radiotherapy in a myeloid-dependent fashion in vivo. CONCLUSION: These data reveal the dynamic, immune-dependent nature of glioblastoma's response to treatments and identify distant NSCs as likely cells of origin.
BACKGROUND: Glioblastoma is a treatment-resistant brain cancer. Its hierarchical cellular nature and its tumor microenvironment (TME) before, during, and after treatments remain unresolved. METHODS: Here, we used single-cell RNA sequencing to analyze new and recurrent glioblastoma and the nearby subventricular zone (SVZ). RESULTS: We found 4 glioblastoma neural lineages are present in new and recurrent glioblastoma with an enrichment of the cancer mesenchymal lineage, immune cells, and reactive astrocytes in early recurrences. Cancer lineages were hierarchically organized around cycling oligodendrocytic and astrocytic progenitors that are transcriptomically similar but distinct to SVZ neural stem cells (NSCs). Furthermore, NSCs from the SVZ of patients with glioblastoma harbored glioblastoma chromosomal anomalies. Lastly, mesenchymal cancer cells and TME reactive astrocytes shared similar gene signatures which were induced by radiotherapy in a myeloid-dependent fashion in vivo. CONCLUSION: These data reveal the dynamic, immune-dependent nature of glioblastoma's response to treatments and identify distant NSCs as likely cells of origin.
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