Rewiring of Integrin Signaling and Cell-cycle Deregulation Drive SMARCB1-Deficient Epithelioid Sarcoma

Miyamoto, R.; Park, J.; Dwosh, G. H.; Zuco, V.; Pasquali, S.; Dickson, B. C.; Kirsch, D. G.

doi:10.64898/2026.09.01.748640

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bioRxiv · 10.64898/2026.09.01.748640

Rewiring of Integrin Signaling and Cell-cycle Deregulation Drive SMARCB1-Deficient Epithelioid Sarcoma

Miyamoto, R.·Park, J.·Dwosh, G. H.·Zuco, V.·Pasquali, S.·Dickson, B. C.·Kirsch, D. G.

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Abstract

Epithelioid sarcoma (EPS) is an aggressive soft-tissue sarcoma characterized by loss of the chromatin-remodeling subunit SMARCB1. The oncogenic programs driving EPS remain poorly understood. Through CRISPR loss-of-function screens, we identified conserved dependencies on integrin signaling components and cyclin-dependent kinases (CDKs). Genetic disruption of integrin subunit alpha V (ITGAV)-centered signaling impaired epithelioid cluster formation and reduced MYC expression. SMARCB1 re-expression phenocopied these effects and revealed that SMARCB1 loss selectively represses context-dependent integrin subunits while preserving an ITGAV-centered pro-survival axis, associated with altered BAF complex occupancy. Analysis of EPS cell lines and primary tumors revealed frequent genetic or epigenetic inactivation of CDKN2A/p16, indicating that loss of cell-cycle control is a key cooperating event in EPS development and providing a mechanistic rationale for targeting CDK4/6. Together, these findings establish integrin-driven oncogenic signaling coupled with disruption of cell-cycle control as a central oncogenic program in EPS and identify actionable therapeutic vulnerabilities.

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Miyamoto, R., Park, J., Dwosh, G. H., Zuco, V., Pasquali, S., Dickson, B. C., Kirsch, D. G.. 2026-09-03. Rewiring of Integrin Signaling and Cell-cycle Deregulation Drive SMARCB1-Deficient Epithelioid Sarcoma. https://doi.org/10.64898/2026.09.01.748640

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