Phosphoproteomic Profiling Identifies Aberrant Activation of Integrin Signaling in Aggressive Non-Type Bladder Carcinoma.

Bladder carcinoma is highly heterogeneous and its complex molecular landscape; thus, poses a significant challenge for resolving an effective treatment in metastatic tumors. We computed the epithelial-mesenchymal transition (EMT) scores of three bladder carcinoma subtypes-luminal, basal, and non-type. The EMT score of the non-type indicated a "mesenchymal-like" phenotype, which correlates with a relatively more aggressive form of carcinoma, typified by an increased migration and invasion. To identify the altered signaling pathways potentially regulating this EMT phenotype in bladder cancer cell lines, we utilized liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based phosphoproteomic approach. Bioinformatics analyses were carried out to determine the activated pathways, networks, and functions in bladder carcinoma cell lines. A total of 3125 proteins were identified, with 289 signature proteins noted to be differentially phosphorylated (p ≤ 0.05) in the non-type cell lines. The integrin pathway was significantly enriched and five major proteins (TLN1, CTTN, CRKL, ZYX and BCAR3) regulating cell motility and invasion were hyperphosphorylated. Our study reveals GSK3A/B and CDK1 as promising druggable targets for the non-type molecular subtype, which could improve the treatment outcomes for aggressive bladder carcinoma.

Journal of clinical medicine. 2019 May 17*** epublish ***

Barnali Deb, Vinuth N Puttamallesh, Kirti Gondkar, Jean P Thiery, Harsha Gowda, Prashant Kumar

Institute of Bioinformatics, International Technology Park, Bangalore 560066, India. ., Institute of Bioinformatics, International Technology Park, Bangalore 560066, India. ., Institute of Bioinformatics, International Technology Park, Bangalore 560066, India. ., Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine NUS Yong Loo Lin School of Medicine, Singapore 117597, Singapore. ., Institute of Bioinformatics, International Technology Park, Bangalore 560066, India. ., Institute of Bioinformatics, International Technology Park, Bangalore 560066, India. .