Final Report Summary - SRLUNG (Steroid Receptors in Non-Small Cell Lung Cancer: Diagnostic, prognostic and therapeutic Implications) Lung cancer is one of the major causes of death worldwide. Therefore, the need for novel biomarkers in diagnosis and potential new therapeutic targets becomes very demanding. Accumulating evidence indicates the relevance of sex steroids in the lung, including cancer. Moreover, gender dichotomy is observed in lung cancer impact, histology, evolution, response to therapy and prognosis. However, the profile and nature of sex steroid receptors in the lung remains controversial. By the Marie Curie CIG- supported SRLUNG project, Dr V. Pelekanou investigated the differential profile and biologic relevance of estrogen receptors in Non-Small Cell Lung Carcinoma (NSCLC). Aim of this study was 1) the identification of i) sex steroid receptors and associated mechanisms in lung cancer biology and 2) their potential application in i) diagnosis and ii) development of novel endocrine-related tailored therapies. With a multiepitope immunohistochemical assay of a large cohort of NSCLC tumors and a novel multiplex ER probe-based transcriptome meta-analysis of (i) >1400 NSCLC and control cases and (ii) 39 NSCLC cell lines she discovered that 1) the wild type ERa is present in only ~10% of cases, while variant receptors (some of which are identified in human lung for the first time) prevail in tumors, 2) While ER action is classically considered mainly nuclear in endocrine-related organs, in the lung ERs mainly localize in extranuclear cellular compartments, suggesting alternative modes of action. Moreover, while in normal lung the expression profile of ERa is gender related, in NSCLC it is the histologic type that defines the type and localization of ERa variants. ERb, which so far was considered the major NSCLC ER, is expressed at lower levels than ER and also shares extranuclear variants. 3) NSCLC also expresses estrogen receptors not encoded by ESR1 gene, like GPR30/GPER. 4) Adenocarcinomas and squamous cell carcinomas display different estrogen receptor profile, reflected also by differential transcriptome gene signatures and signaling pathways (additionally confirmed by transcriptome analysis of estrogen agonists and antagonists in NSCLC cell lines and phenotype changes of cell under E2-agonists). Taken together these results suggest that in NSCLC sex steroid receptors isoforms exert actions distinct from that defined in endocrine related neoplasms, like breast carcinomas. This is of major importance in the differential diagnosis of tumor masses in the lung of unknown origin (primary or metastatic). In addition, the distinct ER in NSCLC histotypes could also be applied in NSCLC subtyping. However, the effects of estrogen effects NSCLC cell lines were controversial, with ER agonists and antagonists expressing different results on cell proliferation and migration, related to the histotype of cells. The results of SRLUNG study provide a clear advance of the state-of-the-art in the field, introducing a possible re-evaluation of the diagnostic criteria of NSCLC, enrolling specific steroid receptors. Additionally, they could set the basis for the establishment of novel prognostic/predictive biomarkers and eventually alternate therapeutic targets. The prestigious Marie Curie CIG Fellowship offered Dr V. Pelekanou a unique opportunity to establish a robust and dynamic career development plan, elaborate working groups and networks, recognition at national and international level, obtain independence and to supervise/train younger scientists and Medical Doctors. Finally, it provided her with Academic Post offers both at the Host Institution, as well as from highly prestigious Universities abroad. Currently she is appointed as Pathology Faculty Staff at Yale University School of Medicine, proud to announce herself as a Marie Curie Alumni, ambassador of European Excellence, as well as a committed young woman in Science. The experience of the Marie Curie Fellowship was definitely a life-time achievement.