124354 20241125101128.0 doi 10.1038/s41416-022-02093-x sideral 132682 ART-2023-132682 eng Juste-Lanas, Y. Universidad de Zaragoza (orcid)0000-0003-2237-8859 3D collagen migration patterns reveal a SMAD3-dependent and TGF-ß1-independent mechanism of recruitment for tumour-associated fibroblasts in lung adenocarcinoma 2023 Access copy available to the general public Unrestricted Background: The TGF-β1 transcription factor SMAD3 is epigenetically repressed in tumour-associated fibroblasts (TAFs) from lung squamous cell carcinoma (SCC) but not adenocarcinoma (ADC) patients, which elicits a compensatory increase in SMAD2 that renders SCC-TAFs less fibrotic. Here we examined the effects of altered SMAD2/3 in fibroblast migration and its impact on the desmoplastic stroma formation in lung cancer. Methods: We used a microfluidic device to examine descriptors of early protrusions and subsequent migration in 3D collagen gels upon knocking down SMAD2 or SMAD3 by shRNA in control fibroblasts and TAFs. Results: High SMAD3 conditions as in shSMAD2 fibroblasts and ADC-TAFs exhibited a migratory advantage in terms of protrusions (fewer and longer) and migration (faster and more directional) selectively without TGF-β1 along with Erk1/2 hyperactivation. This enhanced migration was abrogated by TGF-β1 as well as low glucose medium and the MEK inhibitor Trametinib. In contrast, high SMAD2 fibroblasts were poorly responsive to TGF-β1, high glucose and Trametinib, exhibiting impaired migration in all conditions. Conclusions: The basal migration advantage of high SMAD3 fibroblasts provides a straightforward mechanism underlying the larger accumulation of TAFs previously reported in ADC compared to SCC. Moreover, our results encourage using MEK inhibitors in ADC-TAFs but not SCC-TAFs. info:eu-repo/grantAgreement/ES/AEI-FEDER/SAF2016-79527-R info:eu-repo/grantAgreement/ES/AEI/AEI PID2019-110944RB-I00 info:eu-repo/grantAgreement/ES/FIS FEDER/PS09-02368 info:eu-repo/grantAgreement/ES/ISCIII PI14-01109 info:eu-repo/grantAgreement/ES/ISCIII PI18-00920 info:eu-repo/grantAgreement/ES/MCIU/FPU17-03867 info:eu-repo/grantAgreement/ES/MICINN-AEI-FEDER/PID2021-122409OB-C21 info:eu-repo/grantAgreement/ES/MICINN/RTI2018-094494-B-C21 info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 6.4 2023 ONCOLOGY 46 / 322 = 0.143 2023 Q1 T1 3.0 2023 Oncology 2023 Q1 Cancer Research 2023 Q1 15.1 2023 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Díaz-Valdivia, N. Llorente, A. Ikemori, R. Bernardo, A. Arshakyan, M. Borau, C. Universidad de Zaragoza (orcid)0000-0002-3784-1140 Ramírez, J. Ruffinelli, J. C. Nadal, E. Reguart, N. García-Aznar, J. M. Universidad de Zaragoza (orcid)0000-0002-9864-7683 Alcaraz, J. 1002 050 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Biología Celular 5004 605 Universidad de Zaragoza Dpto. Ingeniería Mecánica Área Mec.Med.Cont. y Teor.Est. 128 (2023), 967-981 Br. J. Cancer BRITISH JOURNAL OF CANCER 0007-0920 4951653 http://zaguan.unizar.es/record/124354/files/texto_completo.pdf Versión publicada 2655535 http://zaguan.unizar.es/record/124354/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:124354 articulos driver 2024-11-22-11:58:17 ARTICLE