3D collagen migration patterns reveal a SMAD3-dependent and TGF-ß1-independent mechanism of recruitment for tumour-associated fibroblasts in lung adenocarcinoma

Juste-Lanas, Y. (Universidad de Zaragoza) ; Díaz-Valdivia, N. ; Llorente, A. ; Ikemori, R. ; Bernardo, A. ; Arshakyan, M. ; Borau, C. (Universidad de Zaragoza) ; Ramírez, J. ; Ruffinelli, J. C. ; Nadal, E. ; Reguart, N. ; García-Aznar, J. M. (Universidad de Zaragoza) ; Alcaraz, J.

Resumen: 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.

Idioma: Inglés

DOI: 10.1038/s41416-022-02093-x

Año: 2023

Publicado en: BRITISH JOURNAL OF CANCER 128 (2023), 967-981
ISSN: 0007-0920

Factor impacto JCR: 6.4 (2023)

Categ. JCR: ONCOLOGY rank: 46 / 322 = 0.143 (2023) - Q1 - T1

Factor impacto SCIMAGO: 3.0 - Oncology (Q1) - Cancer Research (Q1)

Financiación: info:eu-repo/grantAgreement/ES/AEI-FEDER/SAF2016-79527-R
Financiación: info:eu-repo/grantAgreement/ES/AEI/AEI PID2019-110944RB-I00
Financiación: info:eu-repo/grantAgreement/ES/FIS FEDER/PS09-02368
Financiación: info:eu-repo/grantAgreement/ES/ISCIII PI14-01109
Financiación: info:eu-repo/grantAgreement/ES/ISCIII PI18-00920
Financiación: info:eu-repo/grantAgreement/ES/MCIU/FPU17-03867
Financiación: info:eu-repo/grantAgreement/ES/MICINN-AEI-FEDER/PID2021-122409OB-C21
Financiación: info:eu-repo/grantAgreement/ES/MICINN/RTI2018-094494-B-C21

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Biología Celular (Dpto. Bioq.Biolog.Mol. Celular)
Área (Departamento): Área Mec.Med.Cont. y Teor.Est. (Dpto. Ingeniería Mecánica)