title: Snail1-expressing fibroblasts in the tumor microenvironment display mechanical properties that support metastasis.
abstract: 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.
authors.affiliation: Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.
authors.forename: Jelena
authors.initials: J
authors.lastname: Stanisavljevic
authors.affiliation: Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.
authors.forename: Jordina
authors.initials: J
authors.lastname: Loubat-Casanovas
authors.affiliation: Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Majadahonda, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Herrera
authors.affiliation: Unitat de Biofísica i Bioenginyeria, Universitat de Barcelona, Barcelona, Spain. Institute for Bioengineering of Catalonia, Barcelona, Spain.
authors.forename: Tomás
authors.initials: T
authors.lastname: Luque
authors.affiliation: Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Peña
authors.affiliation: Department of Oncology and Hematology, Hospital Clínico Universitario, Valencia, Spain. Department of Medicine, Valencia Central University, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.affiliation: Molecular Therapeutics and Biomarkers in Cancer Laboratory, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar, Barcelona, Spain. Medical Oncology Department, Hospital del Mar, Barcelona, Spain. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.affiliation: Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Majadahonda, Madrid, Spain.
authors.forename: Félix
authors.initials: F
authors.lastname: Bonilla
authors.affiliation: Molecular Therapeutics and Biomarkers in Cancer Laboratory, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar, Barcelona, Spain. Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rovira
authors.affiliation: Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Majadahonda, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Peña
authors.affiliation: Unitat de Biofísica i Bioenginyeria, Universitat de Barcelona, Barcelona, Spain. Institute for Bioengineering of Catalonia, Barcelona, Spain. Ciber Enfermedades Respiratorias (CIBERES), 07110-Bunyola, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Navajas
authors.affiliation: Molecular Therapeutics and Biomarkers in Cancer Laboratory, Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar, Barcelona, Spain. Department of Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain. Department of Pathology, Hospital del Mar, Barcelona, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.affiliation: Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: García de Herreros
authors.affiliation: Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain. jbaulida@imim.es.
authors.forename: Josep
authors.initials: J
authors.lastname: Baulida
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D059016:Tumor Microenvironment; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C066737:RHOA protein, human; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein