Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation.

Clinical management of malignant pleural mesothelioma (MPM) is very challenging because of the uncommon resistance of this tumortochemotherapy. Wereporthereincreased expressionofmacrophage colony-stimulating-factor-1-receptor(M-CSF/CSF-1R) mRNA in mesothelioma versus normal tissue specimens and demonstrate that CSF-1R expression identifies chemoresistant cells of mesothelial nature in both primary cultures and mesothelioma cell lines. By using RNAi or ligand trapping, we demonstrate that the chemoresistance properties of those cells depend on autocrine CSF-1R signaling. At the single-cell level, the isolated CSF-1R pos cells exhibit a complex repertoire of pluripotency, epithelial‐mesenchymal transition and detoxifying factors, which define a clonogenic, chemoresistant, precursor-like cell sub-population. The simple activation of CSF-1R in untransformed mesothelial cells is sufficient to confer clonogenicity and resistance to pemetrexed, hallmarks of mesothelioma. Inaddition,thisinducedageneexpressionprofilehighlymimickingthatobservedintheMPMcellsendogenouslyexpressingthe receptor and the ligands, suggesting that CSF-1R expression is mainly responsible for the phenotype of the identified cell sub-populations. The survival of CSF1R pos cells requires active AKT (v-akt murine thymoma viral oncogene homolog 1)