SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma

Roodolph St Pierre; Clayton K Collings; Daniel D Samé Guerra; Christian J Widmer; Olubusayo Bolonduro; Nazar Mashtalir; Akshay Sankar; Yu Liang; Wenya Linda Bi; Erica H Gerkes; Vijaya Ramesh; Jun Qi; Miriam J Smith; David M Meredith; Cigall Kadoch

doi:10.1038/s41588-022-01077-0

SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma

Nat Genet. 2022 Jun;54(6):861-873. doi: 10.1038/s41588-022-01077-0. Epub 2022 Jun 9.

Authors

Roodolph St Pierre^#^{1

2

3}, Clayton K Collings^#^{1

2}, Daniel D Samé Guerra^{1

2}, Christian J Widmer^{1

2}, Olubusayo Bolonduro^{1

2}, Nazar Mashtalir^{1

2}, Akshay Sankar^{1

2}, Yu Liang⁴, Wenya Linda Bi⁵, Erica H Gerkes⁶, Vijaya Ramesh⁷, Jun Qi⁴, Miriam J Smith^{8

9}, David M Meredith¹⁰, Cigall Kadoch^{11

12}

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Chemical Biology Program, Harvard University, Cambridge, MA, USA.
⁴ Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁵ Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁷ Department of Neurology and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁸ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals Foundation Trust, Manchester, UK.
⁹ Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, UK.
¹⁰ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. [email protected].
¹² Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].

^# Contributed equally.

PMID: 35681054
DOI: 10.1038/s41588-022-01077-0

Abstract

Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes establish and maintain chromatin accessibility and gene expression, and are frequently perturbed in cancer. Clear cell meningioma (CCM), an aggressive tumor of the central nervous system, is uniformly driven by loss of SMARCE1, an integral subunit of the mSWI/SNF core. Here, we identify a structural role for SMARCE1 in selectively stabilizing the canonical BAF (cBAF) complex core-ATPase module interaction. In CCM, cBAF complexes fail to stabilize on chromatin, reducing enhancer accessibility, and residual core module components increase the formation of BRD9-containing non-canonical BAF (ncBAF) complexes. Combined attenuation of cBAF function and increased ncBAF complex activity generates the CCM-specific gene expression signature, which is distinct from that of NF2-mutated meningiomas. Importantly, SMARCE1-deficient cells exhibit heightened sensitivity to small-molecule inhibition of ncBAF complexes. These data inform the function of a previously elusive SWI/SNF subunit and suggest potential therapeutic approaches for intractable SMARCE1-deficient CCM tumors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Chromatin
Chromatin Assembly and Disassembly / genetics
Mammals / genetics
Meningeal Neoplasms* / genetics
Meningioma* / genetics
Transcription Factors / metabolism

Substances

Chromatin
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding