Aproximaciones moleculares para la identificación de nuevos biomarcadores y dianas terapéuticas del cáncer de pulmón no microcítico: células madre tumorales, transición epitelial-mesenquimal y modelos de xenoinjertos derivados de pacientes

Abstract

Lung cancer is the most frequent and the most mortal tumor in absolute terms, accounting for up to more than 18% of cancer deaths worldwide per year.Non-small cell lung cancer (NSCLC) accounts for almost 85% of all lung tumors. The most predominant NSCLC subtypes are lung adenocarcinoma (ADC, 40-45% of all lung cancer cases), and squamous cell carcinoma of the lung (SCC, 25-30% of all lung cancer cases). In addition, lung cancer has a five-year survival rate of less than 20%, partly due to its late diagnosis and acquired resistance to treatments. In recent years, thanks to new genome sequencing technologies,xxiv On the other hand, the effect of TGF-β1 treatment in tumorspheres formation was also analyzed. The results showed that TGF-β1 induces sphericity in 3D culture derived from A549 and H441 cell lines. This suggests that TGF-β1-mediated signaling could promote the CSC population in these cell lines. It also suggests that there is a relationship between the epithelial-mesenchymal transition (EMT) induced by TGF-β1 and CSC features.In collaboration with the Molecular Oncology group of the Research Foundation of the General University Hospital of Valencia (FIHGUV), led by Dr. Camps and Dr. Jantus, the expression analysis of genes involved in EMT and CSC in SPH and ADH cells derived from tumors of NSCLC patients and cell lines was performed. As a result, a novel CSC gene signature was proposed. These analyses showed that the expression of CDKN1A, NOTCH3, CD44, NANOG, SNAI1 and ITGA6 were higher in SPH, and therefore the combined expression of these genes could help to identify the subpopulation of CSC in NSCLC tumors. By correlating the expression of these genes with the survival of the patients, a signature with prognostic value in ADC was obtained based on the expression of CDKN1A, SNAI1 and ITGA6.In this work, it has also been addressed the study of the role of several proteins involved in the EMT whose expression could promote cell migration and invasion in NSCLC, such as the JunB transcription factor and the eIF5A2 translation factor.JunB is a member of the AP-1 transcription complex. AP-1 is a physiological regulator of immediate early signals essential for cell proliferation, survival, differentiation, and responses to environmental stress. Previous studies carried out in our laboratory in U2OS osteosarcoma cells showed that JunB is involved in cell cycle regulation. In addition, new putative JunB targets involved in EMT were identified by chromatin immunoprecipitation and transcriptomic assays. In this work, the A549 cell line was used to analyze whether the role of JunB in TGF-β1-induced EMT was also conserved in NSCLC. The results showed that JunB could be mediating the initiation of the EMT induced by TGF-β1 by regulating the expression of its transcriptional targets, and therefore its activity could be relevant in cancer progression.On the other hand, the translation factor eIF5A2 is also of interest because its overexpression has been observed in several cancers, including NSCLC, and is xxv associate...