Aberrant TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression through CD63 in lung adenocarcinoma

Duch, Paula; Díaz-Valdivia, Natalia; Ikemori, Rafael; Gabasa, Marta; Radisky, Evette S.; Arshakyan, Marselina; Gea‐Sorlí, Sabrina; Mateu-Bosch, Anna; Bragado, Paloma; Carrasco, Josep Lluís; Mori, Hidetoshi; Ramírez, Josep; Teixidó, Cristina; Reguart, Noemı́; Fillat, Cristina; Radisky, Derek C.; Alcaraz, Jordi

doi:10.1016/j.matbio.2022.06.009

Cited by 16 publications

(35 citation statements)

References 55 publications

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“…Consistently, ADC-TAFs but not SCC-TAFs exhibited a positive response to the antifibrotic drug nintedanib in culture [10], thereby mimicking the therapeutic benefits reported by nintedanib in ADC but not in SCC patients in the LUME-1 clinical trial [11]. Likewise, both the lower expression of fibrosis markers and the poor nintedanib response of SCC-TAFs could be reproduced in normal fibroblasts upon knocking down SMAD3 with shRNA, whereas knocking down SMAD2 had opposite effects, supporting that shSMAD2 and shSMAD3 fibroblasts exhibit ADC-like and SCClike phenotypes, respectively [9,12].…”

Section: Introductionmentioning

confidence: 72%

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

et al. 2022

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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.

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Section: Introductionmentioning

confidence: 72%

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

et al. 2022

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“…In agreement with this interpretation, genetic loss-or gain-of-function of SMAD3 levels in TAFs and control fibroblasts were sufficient to decrease or increase the nintedanib-induced reduction of TIMP-1 secretion, respectively. Elevated whole tissue TIMP1 mRNA levels have been reported in lung ADC compared to paired control tissue 20 and in IPF compared to control pulmonary samples. However, nintedanib failed to demonstrate robust therapeutic benefits in trials involving other solid tumors with elevated whole tissue TIMP1 mRNA levels, including lung mesothelioma, colon cancer, or breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Tissue inhibitor of metalloproteinase‐1 is a multifunctional secreted protein typically found within the stroma 18 that has been linked to poor prognosis in NSCLC and virtually all solid tumors 19 . Overexpression of TIMP‐1 in ADC correlates with poor prognosis, and TIMP‐1 has been identified as a key factor in a TAF–cancer cell cross‐talk selectively in ADC 20 . Moreover, previous research showed that TIMP‐1 is inhibited by nintedanib in an animal model of pulmonary fibrosis 21 .…”

Section: Introductionmentioning

confidence: 99%

Aberrant TIMP‐1 production in tumor‐associated fibroblasts drives the selective benefits of nintedanib in lung adenocarcinoma

Duch,

Díaz‐Valdivia,

Gabasa

et al. 2024

Cancer Science

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The fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor‐associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified. Here we examined the role of tissue inhibitor of metalloproteinase‐1 (TIMP‐1), a tumor‐promoting cytokine overproduced in ADC‐TAFs. To this aim, we combined genetic approaches with in vitro and in vivo preclinical models based on patient‐derived TAFs. Nintedanib reduced TIMP‐1 production more efficiently in ADC‐TAFs than SCC‐TAFs through a SMAD3‐dependent mechanism. Cell culture experiments indicated that silencing TIMP1 in ADC‐TAFs abolished the therapeutic effects of nintedanib on cancer cell growth and invasion, which were otherwise enhanced by the TAF secretome. Consistently, co‐injecting ADC cells with TIMP1‐knockdown ADC‐TAFs into immunocompromised mice elicited a less effective reduction of tumor growth and invasion under nintedanib treatment compared to tumors bearing unmodified fibroblasts. Our results unveil a key mechanism underlying the selective mode of action of nintedanib in ADC based on the excessive production of TIMP‐1 in ADC‐TAFs. We further pinpoint reduced SMAD3 expression and consequent limited TIMP‐1 production in SCC‐TAFs as key for the resistance of SCC to nintedanib. These observations strongly support the emerging role of TIMP‐1 as a critical regulator of therapy response in solid tumors.

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“…In fact, TIMP-1 released by CAFs promotes the migration and spread of cancer cells [ 101 ]. In lung adenocarcinoma, it was demonstrated that SMAD3/TIMP-1 in CAFs and CD63 in cancer cells were necessary to drive tumour progression in vitro and in vivo [ 102 ]. In another study, CAF-derived TIMP-1 promoted the migration of a colon cancer cell line, whereas TIMP-1 neutralization inhibited the enhanced migration, and TIMP-1 secretion was higher in CAFs co-cultured with cancer cells than in monocultured CAFs [ 103 ] ( Table 1 ).…”

Section: Cafs Biomarkers: a Mixed Bagmentioning

confidence: 99%

Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives

Toledo

Picón-Ruiz

Marchal

et al. 2022

IJMS

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Tumours are complex systems with dynamic interactions between tumour cells, non-tumour cells, and extracellular components that comprise the tumour microenvironment (TME). The majority of TME’s cells are cancer-associated fibroblasts (CAFs), which are crucial in extracellular matrix (ECM) construction, tumour metabolism, immunology, adaptive chemoresistance, and tumour cell motility. CAF subtypes have been identified based on the expression of protein markers. CAFs may act as promoters or suppressors in tumour cells depending on a variety of factors, including cancer stage. Indeed, CAFs have been shown to promote tumour growth, survival and spread, and secretome changes, but they can also slow tumourigenesis at an early stage through mechanisms that are still poorly understood. Stromal–cancer interactions are governed by a variety of soluble factors that determine the outcome of the tumourigenic process. Cancer cells release factors that enhance the ability of fibroblasts to secrete multiple tumour-promoting chemokines, acting on malignant cells to promote proliferation, migration, and invasion. This crosstalk between CAFs and tumour cells has given new prominence to the stromal cells, from being considered as mere physical support to becoming key players in the tumour process. Here, we focus on the concept of cancer as a non-healing wound and the relevance of chronic inflammation to tumour initiation. In addition, we review CAFs heterogeneous origins and markers together with the potential therapeutic implications of CAFs “re-education” and/or targeting tumour progression inhibition.

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Aberrant TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression through CD63 in lung adenocarcinoma

Cited by 16 publications

References 55 publications

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

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

Aberrant TIMP‐1 production in tumor‐associated fibroblasts drives the selective benefits of nintedanib in lung adenocarcinoma

Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives

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