SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma
Menée à l'aide de lignées cellulaires, d'échantillons de tissus sains et de tissus tumoraux issus de méninges d'origine humaine, cette étude analyse le rôle structurel de la sous-unité SMARCE1 du noyau du complexe mSWI//SNF et démontre que les cellules de méningiomes à cellules claires présentant une déficience de l'expression de SMARCE1 sont sensibles aux perturbations de la forme non canonique du complexe BAF
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.
Nature Genetics , résumé, 2022