Circulating Lung Tumor Cells Capture Extracellular Vesicles Conferring Resistance Phenotype By The Occurrence Of Epithelial-Mesenchymal Transition Reprogramming

Abstract Background: The overall prognosis of lung cancer patients remains dismal, in particular at advanced stages. Only complete surgical resection of early-stage tumors improves the prognosis of certain non-small cell lung cancer (NSCLC) patients. However, migration of circulating tumor cells (CTCs) into the blood stream is probably an early event of carcinogenesis inducing metastases. The fact that some of these CTCs could survive within this “liquid environment” suggest that they acquire phenotypic changes that would confer them improved resistance against anoikis. In this context, we looked if immune blood cells could transfer to CTCs some factors associated with this increased resistance. Materials and Methods: Lung cancer cells (A549 cell line) were incubated with different sub-population of blood cells (PBMCs, granulocytes, platelets) and serum to look for potential transfer of extracellular vesicles (EVs) into the cancer cells. To assess the inter-cell transfer we looked for the presence of a validated blood cell specific marker the miR-223 that should not be expressed in lung cancer cells. By using a direct method for CTCs detection and characterization, we looked for these biomarkers within CTCs of lung cancer patients with early and late stages. Moreover the quantification of these biomarkers was correlated with the expression of vimentin, cytokeratin and E-cadherin Results: First, A549 cells were able to quickly capture microRNA (in particular miR-223) within the control blood samples. We then identified neutrophils as a major source of these miRNA. The inter-cell transfer was EVs dependent and promoted improved resistance and survival of A549 cells cancer cells. In NSCLC patients with different stages, the presence of some specific miRNAs for blood cells was detected in a subpopulation of CTCs showing epithelial to mesenchymal phenotype, in particular an increase of vimentin expression and loss of E-cadherin expression. Conclusion: These results tend to prove that CTCs may capture extracellular vesicles from immune blood cells within the bloodstream and this phenomenon may be associated with a more aggressive phenotype. Inhibition of specific EVs transfer could be on interest for development of new targeted immunotherapies. Citation Format: Josephine Zangari, Marius Ilie, Simon Heeke, Véronique Hofman, Baharia Mograbi, Sophie Raynaud, Salome Lalvee, Nathalie Yazbeck, Charles-Hugo Marquette, Sylvie Leroy, Patrick Brest, Paul Hofman. Circulating lung tumor cells capture extracellular vesicles conferring resistance phenotype by the occurrence of epithelial-mesenchymal transition reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 867. doi:10.1158/1538-7445.AM2017-867