Mechanical ventilation promotes lung tumour spread by modulation of cholesterol cell content

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.

Association of lipid-lowering drug targets with risk of cutaneous melanoma: a mendelian randomization study

“…Current studies also highlight the potential of curcumin in inhibiting PCSK9's effect on cutaneous melanoma by regulating oxidative stress-related signaling pathways [33]. PCSK9's involvement in the development and metastasis of lung and liver melanomas, through LDLR or other mechanisms [34,35], underscores the potential of PCSK9 inhibitors in reducing melanoma risk and improving prognosis.…”

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

“… 334 , 350 , 351 Elevated PCSK9 expression has also been reported to be instrumental in promoting the metastasis and invasiveness of lung cancer and melanoma (specifically within the lung). 352 , 353 In addition, a clinical cohort study involving 44 elderly patients with non-small-cell lung cancer (NSCLC), who were treated with the ICI, nivolumab, revealed that NSCLC patients with lower levels of blood PCSK9 ( < 95 ng/mL) enjoyed a significantly prolonged OS during the second therapeutic cycle. 354 These findings were reinforced in a recent report where advanced NSCLC patients exhibiting low baseline plasma PCSK9 levels gained the most benefit from ICI therapy.…”

“… 344 Moreover, a PCSK9-enriched microenvironment induced by either mechanical ventilation or Ahnak could significantly facilitate melanoma cells to metastasize into the lung in mouse B16F10 melanoma models, which could be rescued by genetic deletion of PCSK9 or an anti-PCSK9 mAb. 352 , 353 Hence, targeting PCSK9 may be a robust and novel strategy to effectively restrict invasion and metastasis in various cancers. (Fig.…”

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“…Cholesterol is an essential component of cell membranes that plays a wide range of physiological roles in the body [ 10 ]. Furthermore, changes in the cholesterol content of the cell membrane directly influence tumor cell stiffness [ 11 ]. The physical properties exhibited on the surface of target cells can potentially influence the dynamic interactions between tumor and T cells [ 12 ].…”