Abstract
Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition.
Highlights
Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity
The dichotomous phenotype of primary and metastatic pleural tumours, some of which are associated with an MPE whereas others are not, is of paramount clinical importance, and prompted us to hypothesize that a causative molecular signature underlines MPE formation[2,3,4]
We show that cancer cells bearing different KRAS mutations cause MPE upon pleural dissemination and that mutant KRAS is important for experimental MPE development
Summary
Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. Mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. Our previous work on experimental mouse models of MPE revealed that pleural tumour-secreted C–C motif chemokine ligand 2 (CCL2) mediates MPE formation by stimulating angiogenesis and vascular leakage and by driving myeloid cells, including monocytes and mast cells, from the bone marrow to the pleural metastatic milieu[5,6,7]. We show that KRAS mutations are detectable in human MPE by careful analyses of Sanger sequencing traces and that mutant KRAS-mediated MPE is actionable
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