Data from Constitutive Activation of Myosin-Dependent Contractility Sensitizes Glioma Tumor-Initiating Cells to Mechanical Inputs and Reduces Tissue Invasion

• DOI: 10.1158/0008-5472.c.6507473.v1
• Publication Date: 2023-04-01T01:29:40Z
• Authors: Sophie Y. Wong; Theresa A. Ulrich; Loic P. Deleyrolle; Joanna L. MacKay; Jung-Ming G. Lin; Regina T. Martusc...; Musa A. Jundi; Brent A. Reynolds; Sanjay Kumar
• Keywords: Contractility

<div>Abstract<p>Tumor-initiating cells (TIC) perpetuate tumor growth, enable therapeutic resistance, and drive initiation of successive tumors. Virtually nothing is known about the role mechanotransductive signaling in controlling TIC tumorigenesis, despite recognized importance altered mechanics tissue dysplasia common observation that extracellular matrix (ECM) stiffness strongly regulates cell behavior. To address this open question, we cultured primary human glioblastoma (GBM) TICs on laminin-functionalized ECMs spanning a range stiffnesses. Surprisingly, found these were largely insensitive to ECM cues, evading inhibition spreading, migration, proliferation typically imposed by compliant ECMs. We hypothesized insensitivity may result from insufficient generation myosin-dependent contractile force. Indeed, both pharmacologic genetic activation contractility through RhoA GTPase, Rho-associated kinase, or myosin light chain kinase restored stiffness-dependent spreading motility, with adopting expected rounded nonmotile phenotype soft Moreover, constitutive restricted three-dimensional invasion spheroid implantation Transwell paradigms. Orthotopic xenotransplantation studies revealed control formed tumors classical GBM histopathology including diffuse infiltration secondary foci, whereas expressing constitutively active mutant produced circumscribed masses yielded 30% enhancement mean survival time. This first direct evidence manipulation can alter tumor-initiating capacity TICs, supporting further exploration signals as potential targets predictors within heterogeneous populations. <i>Cancer Res; 75(6); 1113–22. ©2015 AACR</i>.</p></div>