Abstract Squamous cell carcinomas and adenocarcinomas are the most frequent forms of lung carcinoma, and have different prognoses and therapeutic approaches. During recent years, accumulating evidence has supported an important role of several junctional proteins in carcinogenesis, tumor invasion and metastasis. Contact between epithelial cells is mediated by several types of cell-cell junction, which are composed by complex arrays of transmembrane and plaque proteins and are connected typically to cytoskeletal components. Desmosomes are cell-cell complexes found primarily in epithelial tissues. In addition to the well-known structural role of desmosome genes, evidences such as their dual subcellular location, the interaction with single-stranded DNA and translation initiation factors, etc. suggest there is a poorly understood role of these proteins in signalling pathways. Desmosomal components have been traditionally considered as tumoral suppressors although current evidences suggest potential pro-oncogenic functions of desmosomal-plaque proteins, probably due to an unknown regulatory role in intracellular signaling -such as in Wnt and Akt pathways. Previously, our group showed differentially expressed gene sequences corresponding to several desmosomal plaque-related proteins as a function of tumor type, stage and differentiation grade in NSCLC. The staining pattern of some junctional proteins also differed between squamous-cell carcinomas and adenocarcinomas. Expression of these proteins marked intercellular junctions that are characteristic of the squamous stratum of stratified flattened epithelium and of neoplasias with this type of differentiation. We observed more intense staining of these proteins in better-differentiated areas. In order to gain greater insight into the specific function of some desmosomal components in NSCLC tumors, we have performed several functional assays, as cell cycle and proliferation among others, in selected SCC lung cancer cell lines. Furthermore, we are developing stable cell lines with over-expression and knockdown of some desmosomal proteins by lentiviral vectors and inducible clonal cell lines; and also carrying out knockout cell lines using CRISPR-Cas9 system. Presumably, they will allow us to perform long-term functional assays and expression arrays in order to identify subcellular location and potential pro-oncogenic roles of desmosomal proteins in NSCLC carcinogenesis which may lead to improvements in the treatment and prevention of this disease. Our preliminary results indicate some desmosomal proteins as potential targets for NSCLC diagnosis and treatment. In a future perspective, xenografts will lead to understand the molecular origins and progression of lung cancer in regard to structural components of the desmosome. Corresponding authors: pedromedina@ugr.es, efarez@ugr.es Citation Format: Pedro P. Medina, Laura Boyero, Joel Martin-Padrón, Esther Farez. Pro-oncogenic role of desmosomal plaque-related proteins in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5052.