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2022_BriJouCan_3Dcollagen_AlcarazJ.pdf (4.73 MB)

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2022-12-26

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cc by (c) Juste Lanas, Yago et al., 2022
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/193843

3D collagen migration patterns reveal a SMAD3-dependent and TGF-β1-independent mechanism of recruitment for tumour-associated fibroblasts in lung adenocarcinoma

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Recurs relacionat

https://doi.org/10.1038/s41416-022-02093-x

Resum

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.

Matèries

Epigenètica, Càncer de pulmó, Fibroblasts

Matèries (anglès)

Epigenetics, Lung cancer, Fibroblasts

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Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))

Citació

JUSTE LANAS, Yago, DÍAZ VALDIVIA, Natalia, LLORENTE, Alejandro, IKEMORI, Rafael, BERNARDO, Alejandro, ARSHAKYAN, Marselina, BORAU, Carlos, RAMÍREZ RUZ, J. (josé), RUFFINELLI, José carlos, NADAL, Ernest, REGUART, Noemí, GARCÍA AZNAR, José manuel, ALCARAZ CASADEMUNT, Jordi. 3D collagen migration patterns reveal a SMAD3-dependent and TGF-β1-independent mechanism of recruitment for tumour-associated fibroblasts in lung adenocarcinoma. _British Journal of Cancer_. 2022. Vol. 128, núm. 6, pàgs. 967-981. [consulta: 8 de gener de 2026]. ISSN: 1532-1827. [Disponible a: https://hdl.handle.net/2445/193843]

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