3D collagen migration patterns reveal a SMAD3-dependent and TGF-beta1-independent mechanism of recruitment for tumour-associated fibroblasts in lung adenocarcinoma
Menée à l'aide d'un dispositif microfluidique, d'un gel de collagène ainsi que d'échantillons tumoraux et de fibroblastes pulmonaires issus de patients atteints d'un cancer du poumon non à petites cellules, cette étude met en évidence un mécanisme de recrutement des fibroblastes associés à la tumeur qui dépend du facteur de transcription SMAD3 mais pas du facteur de croissance TGF-bêta1
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
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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
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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
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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.