Abstract
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 tumors have not been explored. To characterize the influence of mechanical ventilation on the behavior of lung tumors, 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 mechano-dependent 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 non-ventilated patients. 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 PCSK9 and LDLR expression, a decrease in intracellular cholesterol and preservation of cell stiffness. A course of mechanical ventilation in mice harboring melanoma implants increased brain and kidney metastases two 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 tumors and the incidence of metastasis, thus decreasing survival. 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.
Footnotes
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Conflict of Interest: Inés López-Alonso reports Postdoctoral Fellowship from Ministerio de Ciencia, Innovación y Universidades, Spanish Government, outside the submitted work.
Conflict of Interest: Cecilia López-Martínez reports PhD grant to institution from Ministerio de Universidades, Spain; Student grant from AECC (Asociación Española Contra el Cáncer), outside the submitted work.
Conflict of Interest: Laura Amado-Rodríguez reports Postdoctoral fellowship to institution from Instituto de Salud Carlos III, Spain; Mobility grant from CIBERES. Instituto de Salud Carlos III, Spain, outside the submitted work.
Conflict of Interest: Aurora Astudillo González reports coordination of national platform Biobank and Biomodels ISCIII, HUB organoids, outside the submitted work.
Conflict of Interest: Miguel 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.
Conflict of Interest: Guillermo 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.
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- Received May 24, 2021.
- Accepted November 22, 2021.
- Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org