Quantitative Image Analysis of Fibrillar Collagens Reveals Novel Diagnostic and Prognostic Biomarkers and Histotype-Dependent Aberrant Mechanobiology in Lung Cancer

Almici, Enrico; Arshakyan, Marselina; Carrasco, Josep Lluís; Martínez, Andrea; Ramírez, Josep; Enguita, Ana B.; Monsó, Eduard; Montero, Joan; Samitier, J.; Alcaraz, Jordi

doi:10.1016/j.modpat.2023.100155

Cited by 6 publications

(5 citation statements)

References 76 publications

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“…ECM stiffness has been shown to critically regulate the expression of IC molecules. For instance, an increase in collagen fiber density, leading to enhanced matrix stiffness, may stimulate PD-L1 expression, thereby promoting immune evasion in cancers [ 105 , 106 ]. Additionally, a deficiency in SNF5 is associated with an increased presence of tumor-infiltrating CD8 + T cells and a reduction in PD-L1-positive cells in vivo.…”

Section: Targeting Ecm Stiffness For Improving the Efficacy Of Immuno...mentioning

confidence: 99%

Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy

Mai,

Lin,

Lin

et al. 2024

Cell Death Dis

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The interplay between extracellular matrix (ECM) stiffness and the tumor microenvironment is increasingly recognized as a critical factor in cancer progression and the efficacy of immunotherapy. This review comprehensively discusses the key factors regulating ECM remodeling, including the activation of cancer-associated fibroblasts and the accumulation and crosslinking of ECM proteins. Furthermore, it provides a detailed exploration of how ECM stiffness influences the behaviors of both tumor and immune cells. Significantly, the impact of ECM stiffness on the response to various immunotherapy strategies, such as immune checkpoint blockade, adoptive cell therapy, oncolytic virus therapy, and therapeutic cancer vaccines, is thoroughly examined. The review also addresses the challenges in translating research findings into clinical practice, highlighting the need for more precise biomaterials that accurately mimic the ECM and the development of novel therapeutic strategies. The insights offered aim to guide future research, with the potential to enhance the effectiveness of cancer immunotherapy modalities.

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Section: Targeting Ecm Stiffness For Improving the Efficacy Of Immuno...mentioning

confidence: 99%

Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy

Mai,

Lin,

Lin

et al. 2024

Cell Death Dis

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“…A major hallmark of the fibrotic tumor stroma in NSCLC and other solid tumors is the pronounced presence of TAFs. Tumor‐associated fibroblasts drive the excessive deposition of fibrillar collagens and other fibrotic ECM components 7,8 . Transforming growth factor‐β1, a potent activator of fibroblasts, is frequently upregulated in NSCLC, correlating with poor outcomes 9 .…”

Section: Introductionmentioning

confidence: 99%

“…Tumor‐associated fibroblasts drive the excessive deposition of fibrillar collagens and other fibrotic ECM components. 7 , 8 Transforming growth factor‐β1, a potent activator of fibroblasts, is frequently upregulated in NSCLC, correlating with poor outcomes. 9 Despite efforts to develop therapeutic TGF‐β1 inhibitors, their clinical application has been hindered by excessive cardiac toxicities.…”

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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“…This gene upregulation is correlated with ECM stiffness in NSCLC but not in small cell lung carcinomas (SCLC), implying that the tumour‐promoting effects of ECM stiffening may be applicable specifically to lung adenocarcinomas. 3 Lung carcinomas with increased collagen fibre density also exhibit elevated expression of the immune checkpoint molecule, programmed death ligand 1 (PD‐L1). 3 YAP and TAZ affect tumour immunity by modulating the expression of PD‐L1 through tethering to the PD‐L1 promoter and via the TEA domain family member (TEAD) group of transcription factors, respectively.…”

mentioning

confidence: 99%

“… 3 Lung carcinomas with increased collagen fibre density also exhibit elevated expression of the immune checkpoint molecule, programmed death ligand 1 (PD‐L1). 3 YAP and TAZ affect tumour immunity by modulating the expression of PD‐L1 through tethering to the PD‐L1 promoter and via the TEA domain family member (TEAD) group of transcription factors, respectively. YAP and TAZ stimulate immunosuppression in NSCLC; therefore, they can be used in combination regimens with immune checkpoint inhibitors but also as predictive biomarkers in the context of immune checkpoint inhibition.…”

mentioning

confidence: 99%

Are YAP and TAZ valid prognostic signatures for NSCLC patients?

Gargalionis,

Papavassiliou,

Papavassiliou

2023

J Cellular Molecular Medi

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Quantitative Image Analysis of Fibrillar Collagens Reveals Novel Diagnostic and Prognostic Biomarkers and Histotype-Dependent Aberrant Mechanobiology in Lung Cancer

Cited by 6 publications

References 76 publications

Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy

Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy

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

Are YAP and TAZ valid prognostic signatures for NSCLC patients?

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