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

Area of Science:

• Cellular biology
• Molecular oncology
• Epigenetics

Background:

• Mammalian SWI/SNF (mSWI/SNF) complexes regulate chromatin accessibility and gene expression, crucial for cellular function.
• These complexes are frequently altered in various cancers, including aggressive central nervous system tumors.
• Clear cell meningioma (CCM) is characterized by the uniform loss of SMARCE1, a key subunit of the mSWI/SNF core.

Purpose of the Study:

• To elucidate the structural and functional role of SMARCE1 in mSWI/SNF complexes.
• To understand the molecular mechanisms driving CCM pathogenesis.
• To identify potential therapeutic vulnerabilities in SMARCE1-deficient CCM.

Main Methods:

• Biochemical assays to analyze mSWI/SNF complex composition and stability.
• Chromatin accessibility studies using techniques like ATAC-seq.
• Analysis of gene expression profiles in CCM and other meningioma subtypes.
• Assessment of cellular response to small-molecule inhibitors targeting ncBAF complexes.

Main Results:

• SMARCE1 is identified as a critical structural component stabilizing the core-ATPase module of the canonical BAF (cBAF) complex.
• Loss of SMARCE1 in CCM impairs cBAF complex stability on chromatin, reducing enhancer accessibility.
• Residual mSWI/SNF components promote the formation of BRD9-containing non-canonical BAF (ncBAF) complexes.
• The combined dysregulation of cBAF and ncBAF complexes results in a unique gene expression signature in CCM, distinct from NF2-mutated meningiomas.
• SMARCE1-deficient cells demonstrate increased sensitivity to ncBAF complex inhibitors.

Conclusions:

• SMARCE1 plays a crucial structural role in maintaining cBAF complex integrity and function.
• The shift towards ncBAF complexes in SMARCE1-deficient CCM contributes to tumor-specific gene expression.
• Targeting ncBAF complexes represents a promising therapeutic strategy for intractable SMARCE1-deficient CCM.