Rewiring of Integrin Signaling and Cell-cycle Deregulation Drive SMARCB1-Deficient Epithelioid Sarcoma
- 1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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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BibTeX
@misc{miyamoto2026rewiring,
title = {{Rewiring of Integrin Signaling and Cell-cycle Deregulation Drive SMARCB1-Deficient Epithelioid Sarcoma}},
author = {R. Miyamoto and J. Park and G. H. Dwosh and V. Zuco and S. Pasquali and B. C. Dickson and D. G. Kirsch},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748640},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748640v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Rewiring of Integrin Signaling and Cell-cycle Deregulation Drive SMARCB1-Deficient Epithelioid Sarcoma
AU - R. Miyamoto
AU - J. Park
AU - G. H. Dwosh
AU - V. Zuco
AU - S. Pasquali
AU - B. C. Dickson
AU - D. G. Kirsch
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748640
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748640v1
AB - 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.
ER -