Formation of an invasion-permissive matrix requires TGFβ/SNAIL1-regulated alternative splicing of fibronectin

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• dc.contributor.author Franco Valls, Héctor
• dc.contributor.author Tusquets-Uxó, Elsa
• dc.contributor.author Sala Romanyà, Laura, 1989-
• dc.contributor.author Val Casals, Maria
• dc.contributor.author Peña Arranz, Raúl, 1976-
• dc.contributor.author Iaconcig, Alessandra
• dc.contributor.author Villarino, Álvaro
• dc.contributor.author Jiménez-Arriola, Martín
• dc.contributor.author Massó, Pere
• dc.contributor.author Trincado Alonso, Juan Luis, 1987-
• dc.contributor.author Eyras Jiménez, Eduardo
• dc.contributor.author Muro, Andrés F.
• dc.contributor.author Otero, Jorge
• dc.contributor.author García de Herreros, Antonio
• dc.contributor.author Baulida i Estadella, Josep, 1965-
• dc.date.accessioned 2024-03-13T15:40:19Z
• dc.date.available 2024-03-13T15:40:19Z
• dc.date.issued 2023
• dc.description.abstract Background: As in most solid cancers, the emergence of cells with oncogenic mutations in the mammary epithelium alters the tissue homeostasis. Some soluble factors, such as TGFβ, potently modify the behavior of healthy stromal cells. A subpopulation of cancer-associated fibroblasts expressing a TGFβ target, the SNAIL1 transcription factor, display myofibroblastic abilities that rearrange the stromal architecture. Breast tumors with the presence of SNAIL1 in the stromal compartment, and with aligned extracellular fiber, are associated with poor survival prognoses. Methods: We used deep RNA sequencing and biochemical techniques to study alternative splicing and human tumor databases to test for associations (correlation t-test) between SNAIL1 and fibronectin isoforms. Three-dimensional extracellular matrices generated from fibroblasts were used to study the mechanical properties and actions of the extracellular matrices on tumor cell and fibroblast behaviors. A metastatic mouse model of breast cancer was used to test the action of fibronectin isoforms on lung metastasis. Results: In silico studies showed that SNAIL1 correlates with the expression of the extra domain A (EDA)-containing (EDA+) fibronectin in advanced human breast cancer and other types of epithelial cancers. In TGFβ-activated fibroblasts, alternative splicing of fibronectin as well as of 500 other genes was modified by eliminating SNAIL1. Biochemical analyses demonstrated that SNAIL1 favors the inclusion of the EDA exon by modulating the activity of the SRSF1 splicing factor. Similar to Snai1 knockout fibroblasts, EDA- fibronectin fibroblasts produce an extracellular matrix that does not sustain TGFβ-induced fiber organization, rigidity, fibroblast activation, or tumor cell invasion. The presence of EDA+ fibronectin changes the action of metalloproteinases on fibronectin fibers. Critically, in an mouse orthotopic breast cancer model, the absence of the fibronectin EDA domain completely prevents lung metastasis. Conclusions: Our results support the requirement of EDA+ fibronectin in the generation of a metastasis permissive stromal architecture in breast cancers and its molecular control by SNAIL1. From a pharmacological point of view, specifically blocking EDA+ fibronectin deposition could be included in studies to reduce the formation of a pro-metastatic environment.
• dc.description.sponsorship This study was funded by grants awarded to AGH and JB by the Agencia Estatal de Investigación (AEI) del Ministerio de Ciencia e Innovación MCIN (Proyecto PID2019-104698RB-I00 financiado por MCIN/ AEI/10.13039/501100011033, y pProyecto PID2022-136968OB-I00 financiado por MCIN/AEI /10.13039/501100011033/ y por FEDER Una manera de hacer Europa).
• dc.format.mimetype application/pdf
• dc.identifier.citation Franco-Valls H, Tusquets-Uxó E, Sala L, Val M, Peña R, Iaconcig A, Villarino Á, Jiménez-Arriola M, Massó P, Trincado JL, Eyras E, Muro AF, Otero J, García de Herreros A, Baulida J. Formation of an invasion-permissive matrix requires TGFβ/SNAIL1-regulated alternative splicing of fibronectin. Breast Cancer Res. 2023 Nov 14;25(1):143. DOI: 10.1186/s13058-023-01736-y
• dc.identifier.doi http://dx.doi.org/10.1186/s13058-023-01736-y
• dc.identifier.issn 1465-5411
• dc.identifier.uri http://hdl.handle.net/10230/59403
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Breast Cancer Res. 2023 Nov 14;25(1):143
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-104698RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-136968OB-I00
• dc.rights © The Author(s) 2023, corrected publication 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Breast cancer
• dc.subject.keyword EDA+ Fibronectin
• dc.subject.keyword Extracellular matrix
• dc.subject.keyword Matrix architecture
• dc.subject.keyword Matrix rigidity
• dc.subject.keyword Metastasis
• dc.subject.keyword Myofibroblasts
• dc.subject.keyword SNAIL1
• dc.subject.keyword TGFβ
• dc.title Formation of an invasion-permissive matrix requires TGFβ/SNAIL1-regulated alternative splicing of fibronectin
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion