التفاصيل البيبلوغرافية
| العنوان: |
3D collagen migration patterns reveal a SMAD3-dependent and TGF-β1-independent mechanism of recruitment for tumour-associated fibroblasts in lung adenocarcinoma. |
| المؤلفون: |
Juste-Lanas, Yago, Díaz-Valdivia, Natalia, Llorente, Alejandro, Ikemori, Rafael, Bernardo, Alejandro, Arshakyan, Marselina, Borau, Carlos, Ramírez, Josep, Ruffinelli, José Carlos, Nadal, Ernest, Reguart, Noemí, García-Aznar, José M., Alcaraz, Jordi |
| المصدر: |
British Journal of Cancer; Apr2023, Vol. 128 Issue 6, p967-981, 15p |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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