Non-small cell lung cancer map and analysis: exploring interconnected oncogenic signal integrators.

Abstract

Non-Small Cell lung cancer (NSCLC) is known for its fast progression, metastatic potency, and a leading cause of mortality globally. At diagnosis, approximately 30-40% of NSCLC patients already present with metastasis. Epithelial to mesenchymal transition (EMT) is a developmental program implicated in cancer progression and metastasis. Transforming Growth Factor-β (TGFβ) and its signalling plays a prominent role in orchestrating the process of EMT and cancer metastasis. In present study, a comprehensive molecular interaction map of TGFβ induced EMT in NSCLC was developed through an extensive literature survey. The map encompasses 394 species interconnected through 554 reactions, representing the relationship and complex interplay between TGFβ induced SMAD dependent and independent signalling pathways (PI3K/Akt, Wnt, EGFR, JAK/STAT, p38 MAPK, NOTCH, Hypoxia). The map, built using Cell Designer and compliant with SBGN and SBML standards, was subsequently translated into a logical modelling framework using CaSQ and dynamically analysed with Cell Collective. These analyses illustrated the complex regulatory dynamics, capturing the known experimental outcomes of TGFβ induced EMT in NSCLC including the co-existence of hybrid EM phenotype during transition. Hybrid EM phenotype is known to contribute for the phenotypic plasticity during metastasis. Network-based analysis identified the crucial network level properties and hub regulators, while the transcriptome-based analysis cross validated the prognostic significance and clinical relevance of key regulators. Overall, the map developed and the subsequent analyses offer deeper understanding of the complex regulatory network governing the process of EMT in NSCLC.