Abstract

Pilocytic astrocytoma (PA), the most common childhood brain tumor, is a low-grade glioma with a single driver BRAF rearrangement. Here, we perform scRNAseq in six PAs using methods that enabled detection of the rearrangement. When compared to higher-grade gliomas, a strikingly higher proportion of the PA cancer cells exhibit a differentiated, astrocyte-like phenotype. A smaller proportion of cells exhibit a progenitor-like phenotype with evidence of proliferation. These express a mitogen-activated protein kinase (MAPK) programme that was absent from higher-grade gliomas. Immune cells, especially microglia, comprise 40% of all cells in the PAs and account for differences in bulk expression profiles between tumor locations and subtypes. These data indicate that MAPK signaling is restricted to relatively undifferentiated cancer cells in PA, with implications for investigational therapies directed at this pathway.

Details

Title
Mitogenic and progenitor gene programmes in single pilocytic astrocytoma cells
Author
Reitman, Zachary J 1 ; Paolella, Brenton R 2   VIAFID ORCID Logo  ; Bergthold, Guillaume 3 ; Pelton, Kristine 4 ; Becker, Sarah 4 ; Jones, Robert 4 ; Sinai, Claire E 5 ; Malkin, Hayley 6 ; Huang, Ying 4 ; Grimmet, Leslie 7 ; Herbert, Zachary T 7 ; Sun, Yu 6 ; Weatherbee, Jessica L 6 ; Alberta, John A 6 ; Daley, John F 8 ; Rozenblatt-Rosen, Orit 9 ; Condurat, Alexandra L 10 ; Kenin Qian 5 ; Khadka, Prasidda 6 ; Segal, Rosalind A 6 ; Haas-Kogan, Daphne 11 ; Filbin, Mariella G 10 ; Suva, Mario L 12   VIAFID ORCID Logo  ; Regev, Aviv 13 ; Stiles, Charles D 6 ; Kieran, Mark W 14 ; Goumnerova, Liliana 15   VIAFID ORCID Logo  ; Ligon, Keith L 16 ; Shalek, Alex K 17 ; Bandopadhayay, Pratiti 10 ; Beroukhim, Rameen 18   VIAFID ORCID Logo 

 Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA 
 Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA 
 Hoffmann-La Roche, Product Development, Innovative Pediatric Oncology Drug Discovery, Basel, Switzerland; Centre Hospitalier Universitaire Strasbourg, Service Hématologie-Oncologie Pédiatrique, Strasbourg, France 
 Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, USA 
 Department of Pediatric Oncology, Dana-Farber Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA 
 Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA 
 Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA, USA 
 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 
 Broad Institute of MIT and Harvard, Cambridge, MA, USA 
10  Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Pediatric Oncology, Dana-Farber Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA 
11  Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 
12  Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA 
13  Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Biology, Howard Hughes Medical Institute, Koch Institute, MIT, Cambridge, MA, USA 
14  Department of Pediatric Oncology, Dana-Farber Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Bristol-Myers Squibb, Boston, Devens, MA, USA; Bristol-Myers Squibb, Lawrenceville, NJ, USA 
15  Department of Neurosurgery, Boston Children’s Hospital, Boston, MA, USA 
16  Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, USA 
17  Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, USA 
18  Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 
Pages
1-17
Publication year
2019
Publication date
Aug 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2275917183
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.