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Nat Commun. 2019 Aug 19;10(1):3731. doi: 10.1038/s41467-019-11493-2.

Mitogenic and progenitor gene programmes in single pilocytic astrocytoma cells.

Author information

1
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
2
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
3
Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, 02215, USA.
4
Hoffmann-La Roche, Product Development, Innovative Pediatric Oncology Drug Discovery, CH-4070, Basel, Switzerland.
5
Centre Hospitalier Universitaire Strasbourg, Service Hématologie-Oncologie Pédiatrique, 67000, Strasbourg, France.
6
Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
7
Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
8
Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
10
Department of Pediatrics, Harvard Medical School, Boston, MA, 02215, USA.
11
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
12
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
13
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
14
Department of Biology, Howard Hughes Medical Institute, Koch Institute, MIT, Cambridge, MA, 02139, USA.
15
Bristol-Myers Squibb, Boston, Devens, MA, 01434, USA.
16
Bristol-Myers Squibb, Lawrenceville, NJ, 08648, USA.
17
Department of Neurosurgery, Boston Children's Hospital, Boston, MA, 02215, USA.
18
Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
19
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, 02139, USA.
20
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. pratiti_bandopadhayay@dfci.harvard.edu.
21
Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA. pratiti_bandopadhayay@dfci.harvard.edu.
22
Department of Pediatrics, Harvard Medical School, Boston, MA, 02215, USA. pratiti_bandopadhayay@dfci.harvard.edu.
23
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA. rameen_beroukhim@dfci.harvard.edu.
24
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. rameen_beroukhim@dfci.harvard.edu.
25
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. rameen_beroukhim@dfci.harvard.edu.

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.

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