Home > Articles > 3D collagen migration patterns reveal a SMAD3-dependent and TGF-ß1-independent mechanism of recruitment for tumour-associated fibroblasts in lung adenocarcinoma
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 CITESCORE: 15.1 - Cancer Research (Q1) - Oncology (Q1)