American Association for Cancer Research
00085472can141903-sup-133850_1_video_2648991_nbl6nq.avi (3.09 MB)

Supplemetary Video S3 from Snail1-Expressing Fibroblasts in the Tumor Microenvironment Display Mechanical Properties That Support Metastasis

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posted on 2023-03-30, 23:25 authored by Jelena Stanisavljevic, Jordina Loubat-Casanovas, Mercedes Herrera, Tomás Luque, Raúl Peña, Ana Lluch, Joan Albanell, Félix Bonilla, Ana Rovira, Cristina Peña, Daniel Navajas, Federico Rojo, Antonio García de Herreros, Josep Baulida

Video S3. MDA-MB231 cells on 3D-ECM generated by KO MEFs.



Crosstalk between tumor and stromal cells in the tumor microenvironment alter its properties in ways that facilitate the invasive behavior of tumor cells. Here, we demonstrate that cancer-associated fibroblasts (CAF) increase the stiffness of the extracellular matrix (ECM) and promote anisotropic fiber orientation, two mechanical signals generated through a Snail1/RhoA/αSMA–dependent mechanism that sustains oriented tumor cell migration and invasiveness. Snail1-depleted CAF failed to acquire myofibroblastic traits in response to TGFβ, including RhoA activation, αSMA-positive stress fibers, increased fibronectin fibrillogenesis, and production of a stiff ECM with oriented fibers. Snail1 expression in human tumor–derived CAF was associated with an ability to organize the ECM. In coculture, a relatively smaller number of Snail1-expressing CAF were capable of imposing an anisotropic ECM architecture, compared with nonactivated fibroblasts. Pathologically, human breast cancers with Snail1+ CAF tended to exhibit desmoplastic areas with anisotropic fibers, lymph node involvement, and poorer outcomes. Snail1 involvement in driving an ordered ECM was further confirmed in wound-healing experiments in mice, with Snail1 depletion preventing the anisotropic organization of granulation tissue and delaying wound healing. Overall, our results showed that inhibiting Snail1 function in CAF could prevent tumor-driven ECM reorganization and cancer invasion. Cancer Res; 75(2); 284–95. ©2014 AACR.