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

Autor: Duch P; Department of Biomedicine, School of Medicine and Health Sciences, Unit of Biophysics and Bioengineering, University of Barcelona, Barcelona, Spain., Díaz-Valdivia N; Department of Biomedicine, School of Medicine and Health Sciences, Unit of Biophysics and Bioengineering, University of Barcelona, Barcelona, Spain., Gabasa M; Department of Biomedicine, School of Medicine and Health Sciences, Unit of Biophysics and Bioengineering, University of Barcelona, Barcelona, Spain.; Thoracic Oncology Unit, Hospital Clinic Barcelona, Barcelona, Spain., Ikemori R; Department of Biomedicine, School of Medicine and Health Sciences, Unit of Biophysics and Bioengineering, University of Barcelona, Barcelona, Spain., Arshakyan M; Department of Biomedicine, School of Medicine and Health Sciences, Unit of Biophysics and Bioengineering, University of Barcelona, Barcelona, Spain., Fernández-Nogueira P; Department of Biomedicine, School of Medicine and Health Sciences, Unit of Biophysics and Bioengineering, University of Barcelona, Barcelona, Spain., Llorente A; Department of Biomedicine, School of Medicine and Health Sciences, Unit of Biophysics and Bioengineering, University of Barcelona, Barcelona, Spain., Teixido C; Thoracic Oncology Unit, Hospital Clinic Barcelona, Barcelona, Spain.; Pathology Service, Hospital Clinic Barcelona, Barcelona, Spain.; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain., Ramírez J; Thoracic Oncology Unit, Hospital Clinic Barcelona, Barcelona, Spain.; Pathology Service, Hospital Clinic Barcelona, Barcelona, Spain.; Biomedical Research Center Network for Respiratory Diseases (CIBERES), Carlos III Health Institute, Madrid, Spain., Pereda J; Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot, Spain., Chuliá-Peris L; Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot, Spain., Galbis JM; Thoracic Surgery Service, Ribera University Hospital, Alzira, Spain., Hilberg F; Boehringer Ingelheim Austria RCV GmbH & Co. KG, Vienna, Austria., Reguart N; Thoracic Oncology Unit, Hospital Clinic Barcelona, Barcelona, Spain.; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain., Radisky DC; Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA., Alcaraz J; Department of Biomedicine, School of Medicine and Health Sciences, Unit of Biophysics and Bioengineering, University of Barcelona, Barcelona, Spain.; Thoracic Oncology Unit, Hospital Clinic Barcelona, Barcelona, Spain.; Biomedical Research Center Network for Respiratory Diseases (CIBERES), Carlos III Health Institute, Madrid, Spain.; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.
Jazyk: angličtina
Zdroj: Cancer science [Cancer Sci] 2024 May; Vol. 115 (5), pp. 1505-1519. Date of Electronic Publication: 2024 Mar 12.
DOI: 10.1111/cas.16141
Abstrakt: 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.
(© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
Databáze: MEDLINE
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