Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/193843
Title: 3D collagen migration patterns reveal a SMAD3-dependent and TGF-β1-independent mechanism of recruitment for tumour-associated fibroblasts in lung adenocarcinoma
Author: Juste Lanas, Yago
Diaz Valdivia, Natalia
Llorente, Alejandro
Ikemori, Rafael
Bernardo, Alejandro
Arshakyan, Marselina
Borau, Carlos
Ramírez, Josep
Ruffinelli, José Carlos
Nadal, Ernest
Reguart, Noemí
García Aznar, José Manuel
Alcaraz, Jordi
Keywords: Epigenètica
Càncer de pulmó
Fibroblasts
Epigenetics
Lung cancer
Fibroblasts
Issue Date: 26-Dec-2022
Publisher: Springer Nature
Abstract: 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.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.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.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.
Note: Reproducció del document publicat a: https://doi.org/10.1038/s41416-022-02093-x
It is part of: British Journal of Cancer, 2022, vol. 128, num. 6, p. 967-981
URI: http://hdl.handle.net/2445/193843
Related resource: https://doi.org/10.1038/s41416-022-02093-x
ISSN: 1532-1827
Appears in Collections:Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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