Abstract
Background Mechanical stretch of cancer cells can alter their invasiveness. During mechanical ventilation, lungs may be exposed to an increased amount of stretch, but the consequences on lung tumours have not been explored.
Methods To characterise the influence of mechanical ventilation on the behaviour of lung tumours, invasiveness assays and transcriptomic analyses were performed in cancer cell lines cultured in static conditions or under cyclic stretch. Mice harbouring lung melanoma implants were submitted to mechanical ventilation and metastatic spread was assessed. Additional in vivo experiments were performed to determine the mechanodependent specificity of the response. Incidence of metastases was studied in a cohort of lung cancer patients that received mechanical ventilation compared with a matched group of nonventilated patients.
Results Stretch increases invasiveness in melanoma B16F10luc2 and lung adenocarcinoma A549 cells. We identified a mechanosensitive upregulation of pathways involved in cholesterol processing in vitro, leading to an increase in pro-protein convertase subtilisin/kexin type 9 (PCSK9) and LDLR expression, a decrease in intracellular cholesterol and preservation of cell stiffness. A course of mechanical ventilation in mice harbouring melanoma implants increased brain and kidney metastases 2 weeks later. Blockade of PCSK9 using a monoclonal antibody increased cell cholesterol and stiffness and decreased cell invasiveness in vitro and metastasis in vivo. In patients, mechanical ventilation increased PCSK9 abundance in lung tumours and the incidence of metastasis, thus decreasing survival.
Conclusions Our results suggest that mechanical stretch promote invasiveness of cancer cells, which may have clinically relevant consequences. Pharmacological manipulation of cholesterol endocytosis could be a novel therapeutic target in this setting.
Abstract
Even a short course of mechanical ventilation, such as during major surgery, promotes lung cancer dissemination. A mechanodependent modulation of cholesterol intake regulates cancer cell stiffness and could be a new therapeutic target in this setting. https://bit.ly/3G0IbcI
Footnotes
Author contributions: Study design: I. López-Alonso, G.M. Albaiceta and L. Amado-Rodríguez. Cell and animal studies: I. López-Alonso, C. López-Martínez, P. Martín-Vicente, I. Crespo, A. Fueyo and A. Astudillo. RNA sequencing analysis: C. López-Martínez, A. González-López and G.M. Albaiceta. Cell stretch and atomic force microscopy: I. Almendros, H. Sanz-Fraile, J. Otero and R. Farré. Clinical study: J. Mayordomo-Colunga, C. del Busto, M. Bernal, M. Arias-Guillén, L. Amado-Rodríguez and G.M. Albaiceta. Data analysis: I. López-Alonso, C. López-Martínez and G.M. Albaiceta. Manuscript writing: I. López-Alonso and G.M. Albaiceta. Manuscript review and editing: all authors.
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Conflict of Interest: I. López-Alonso reports postdoctoral fellowship from Ministerio de Ciencia, Innovación y Universidades, Spanish Government, outside the submitted work. C. López-Martínez reports PhD grant paid to institution from Ministerio de Universidades, Spain; student grant from AECC (Asociación Española Contra el Cáncer), outside the submitted work. L. Amado-Rodríguez reports postdoctoral fellowship paid to institution from Instituto de Salud Carlos III, Spain; mobility grant from CIBERES, Instituto de Salud Carlos III, Spain, outside the submitted work. A. Astudillo reports coordination of national platform Biobank and Biomodels ISCIII, HUB organoids, outside the submitted work. M. Arias-Guillén reports support for the present manuscript from Spanish Society of Pulmonology and Thoracic Surgery (SEPAR); grants from Carlos III Health Institute, and Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), outside the submitted work. G.M Albaiceta reports support for the present manuscript from Instituto de Salud Carlos III; and holds a patent on a model of mechanical ventilator from Arcelor-Mittal. All other authors have nothing to disclose.
Support statement: Funded by Centro de Investigación Biomédica en Red (CIBER)-Enfermedades Respiratorias (Madrid, Spain, grant CB17/06/0021), Instituto de Salud Carlos III (Madrid, Spain, grants PI13/02189, PI16/01614 and PI20/01360) and Asociación Española Contra el Cancer (PPLVE18060). Instituto Universitario de Oncología del Principado de Asturias is supported by Fundación Liberbank. I. López-Alonso was the recipient of a grant from Ministerio de Ciencia, Innovación y Universidades, Spanish Government (CAS19/00209). C. López-Martínez is the recipient of a grant from Ministerio de Universidades, Spain (FPU18/02965). L. Amado-Rodríguez was the recipient of a grant from Instituto de Salud Carlos III, Spain (CM16/00128) and a mobility grant from CIBERES, Instituto de Salud Carlos III, Spain. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received May 24, 2021.
- Accepted November 22, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
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