3D collagen migration patterns reveal a SMAD3-dependent and TGF-β1-independent mechanism of recruitment for tumour-associated fibroblasts in lung adenocarcinoma.
Humans
Adenocarcinoma
/ pathology
Adenocarcinoma of Lung
Cancer-Associated Fibroblasts
/ metabolism
Collagen
Fibroblasts
/ metabolism
Glucose
/ pharmacology
Lung Neoplasms
/ pathology
Mitogen-Activated Protein Kinase Kinases
Smad2 Protein
/ metabolism
Smad3 Protein
/ metabolism
Transforming Growth Factor beta1
/ metabolism
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
11
03
2022
accepted:
25
11
2022
revised:
19
11
2022
pubmed:
27
12
2022
medline:
15
3
2023
entrez:
26
12
2022
Statut:
ppublish
Résumé
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.
Sections du résumé
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.
Identifiants
pubmed: 36572730
doi: 10.1038/s41416-022-02093-x
pii: 10.1038/s41416-022-02093-x
pmc: PMC10006167
doi:
Substances chimiques
Collagen
9007-34-5
Glucose
IY9XDZ35W2
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Smad2 Protein
0
Smad3 Protein
0
SMAD3 protein, human
0
Transforming Growth Factor beta1
0
TGFB1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
967-981Subventions
Organisme : Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministerio de Economía, Industria y Competitividad)
ID : FPU17/03867
Organisme : Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministerio de Economía, Industria y Competitividad)
ID : RTI2018-094494-B-C21
Organisme : Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministerio de Economía, Industria y Competitividad)
ID : PID2021-122409OB-C21
Organisme : Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministerio de Economía, Industria y Competitividad)
ID : PI13/02368
Organisme : Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministerio de Economía, Industria y Competitividad)
ID : SAF2016-79527-R
Organisme : Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministerio de Economía, Industria y Competitividad)
ID : PID2019-110944RB-I00
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : PI14/01109
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : PI18/00920
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : Adg-101018587
Organisme : Generalitat de Catalunya (Government of Catalonia)
ID : SGR 661
Organisme : Fundación Científica Asociación Española Contra el Cáncer (Scientific Foundation, Spanish Association Against Cancer)
ID : AECC B16-917
Organisme : Sociedad Española de Neumología y Cirugía Torácica (SEPAR)
ID : SEPAR 951/2019
Informations de copyright
© 2022. The Author(s).
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