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Publication Metadata only Altered inflammatory and death pathways in head and neck cell lines model genomic and expression signatures identified in the cancer genome Atlas(American Association for Cancer Research, 2015) Yang, Xinping; Cheng, Hui; Saleh, Anthony; Cornelius, Shaleeka; Nussinov, Ruth; Van Weas, Carter; Chen, Zhong; Department of Computer Engineering; Department of Chemical and Biological Engineering; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Department of Computer Engineering; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745Publication Metadata only Androgen receptor binding sites are highly mutated in prostate cancer(American Association for Cancer Research (AACR), 2018) N/A; Department of Industrial Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; N/A; Morova, Tunç; Gönen, Mehmet; Gürsoy, Attila; Keskin, Özlem; Lack, Nathan Alan; N/A; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Department of Industrial Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; College of Engineering; College of Engineering; College of Engineering; School of Medicine; N/A; 237468; 8745; 26605; 120842Publication Open Access Association of B7-H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer(Wiley, 2022) Mendes, Adrianna A.; Lu, Jiayun; Kaur, Harsimar B.; Zheng, Siqun L.; Xu, Jianfeng; Hicks, Jessica; Weiner, Adam B.; Schaeffer, Edward M.; Ross, Ashley E.; Balk, Steven P.; Taplin, Mary-Ellen; Department of Chemical and Biological Engineering; Lack, Nathan Alan; Tekoğlu, Tahsin Emirhan; Faculty Member; Department of Chemical and Biological Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Sciences and Engineering; 120842; N/ABackground: B7 homolog 3 (B7-H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD-L1. Immunotherapies (antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells) targeting B7-H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7-H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa. Methods: an automated, clinical-grade immunohistochemistry assay was developed by to digitally quantify B7-H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy. Results: B7-H3 protein expression was significantly lower in self-identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7-H3 protein expression with ERG/ETS and PTEN status. B7-H3 messenger RNA expression, but not B7-H3 protein expression, was significantly correlated with regulatory (FOXP3-positive) T-cell density. Finally, androgen receptor activity scores were significantly correlated with B7-H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7-H3 protein expression. Conclusions: the current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7-H3 expression. Lay Summary: B7-H3 is an immunomodulatory molecule that is highly expressed in prostate cancer and is under investigation in clinical trials. The authors determined that B7-H3 protein expression is inversely correlated with an individual's proportion of African ancestry. The results demonstrate that B7-H3 messenger RNA expression is correlated with the density of tumor T-regulatory cells. Finally, in the first paired analysis of B7-H3 protein expression before and after neoadjuvant intensive hormone therapy, the authors determined that hormone therapy is associated with a decrease in B7-H3 protein levels, suggesting that androgen signaling may positively regulate B7-H3 expression. These results may help to guide the design of future clinical trials and to develop biomarkers of response in such trials.Publication Metadata only Head and neck cancers promote an inflammatory transcriptome through coactivation of classic and alternative NF-κB pathways(Amer Assoc Cancer Research, 2019) Yang, Xinping; Cheng, Hui; Chen, Jianhong; Wang, Ru; Saleh, Anthony; Si, Han; Lee, Steven; Nussinov, Ruth; Fang, Jugao; Van Waes, Carter; Chen, Zhong; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745Head and neck squamous cell carcinomas (HNSCC) promote inflammation in the tumor microenvironment through aberrant NF-kappa B activation, but the genomic alterations and pathway networks that modulate NF-kappa B signaling have not been fully dissected. Here, we analyzed genome and transcriptome alterations of 279 HNSCC specimens from The Cancer Genome Atlas (TCGA) cohort and identified 61 genes involved in NF-kappa B and inflammatory pathways. The top 30 altered genes were distributed across 96% of HNSCC samples, and their expression was often correlated with genomic copy-number alterations (CNA). Ten of the amplified genes were associated with human papilloma virus (HPV) status. We sequenced 15 HPV- and 11 HPV+ human HNSCC cell lines, and three oral mucosa keratinocyte lines, and supervised clustering revealed that 28 of 61 genes exhibit altered expression patterns concordant with HNSCC tissues and distinct signatures related to their HPV status. RNAi screening using an NF-kappa B reporter line identified 16 genes that are induced by TNF alpha or Lymphotoxin-beta (LT beta) and implicated in the classic and/or alternative NF-kappa B pathways. Knockdown of TNFR, LTBR, or selected downstream signaling components established cross-talk between the classic and alternative NF-kappa B pathways. TNF alpha and LT beta induced differential gene expression involving the NF-kappa B, IFN gamma, and STAT pathways, inflammatory cytokines, and metastasis-related genes. Improved survival was observed in HNSCC patients with elevated gene expression in T-cell activation, immune checkpoints, and IFN gamma and STAT pathways. These gene signatures of NF-kappa B activation, which modulate inflammation and responses to the immune therapy, could serve as potential biomarkers in future clinical trials.Publication Open Access Quantitative proteomics identifies secreted diagnostic biomarkers as well as tumor-dependent prognostic targets for clear cell Renal Cell Carcinoma(American Association for Cancer Research (AACR), 2021) Erdem, Selçuk; Bağbudar, Sidar; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Şentürk, Aydanur; Şahin, Ayşe Tuğçe; Armutlu, Ayşe; Kiremit, Murat Can; Acar, Ömer; Esen, Tarık; Tunçbağ, Nurcan; Faculty Member; Teaching Faculty; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; College of Sciences; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; School of Medicine; College of Engineering; 105301; N/A; N/A; 133567; N/A; 237530; 50536; 245513Clear cell renal cell carcinoma (ccRCC) is the third most common and most malignant urological cancer, with a 5-year survival rate of 10% for patients with advanced tumors. Here, we identified 10,160 unique proteins by in-depth quantitative proteomics, of which 955 proteins were significantly regulated between tumor and normal adjacent tissues. We verified four putatively secreted biomarker candidates, namely, PLOD2, FERMT3, SPARC, and SIRPa, as highly expressed proteins that are not affected by intratumor and intertumor heterogeneity. Moreover, SPARC displayed a significant increase in urine samples of patients with ccRCC, making it a promising marker for the detection of the disease in body fluids. Furthermore, based on molecular expression profiles, we propose a biomarker panel for the robust classification of ccRCC tumors into two main clusters, which significantly differed in patient outcome with an almost three times higher risk of death for cluster 1 tumors compared with cluster 2 tumors. Moreover, among the most significant dustering proteins, 13 were targets of repurposed inhibitory FDA-approved drugs. Our rigorous proteomics approach identified promising diagnostic and tumor-discriminative biomarker candidates which can serve as therapeutic targets for the treatment of ccRCC. Implications: Our in-depth quantitative proteomics analysis of ccRCC tissues identifies the putatively secreted protein SPARC as a promising urine biomarker and reveals two molecular tumor phenotypes.Publication Metadata only The key role of calmodulin in kras-driven adenocarcinomas(Amer Assoc Cancer Research, 2015) Nussinov, Ruth; Tsai, Chung-Jung; Jang, Hyunbum; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Muratçıoğlu, Serena; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745KRAS4B is a highly oncogenic splice variant of the KRAS isoform. It is the only isoform associated with initiation of adenocarcinomas. Insight into why and how KRAS4B can mediate ductal adenocarcinomas, particularly of the pancreas, is vastly important for its therapeutics. Here we point out the overlooked critical role of calmodulin (CaM). Calmodulin selectively binds to GTP-bound K-Ras4B; but not to other Ras isoforms. Cell proliferation and growth require the MAPK (Raf/MEK/ERK) and PI3K/Akt pathways. We propose that Ca2+/calmodulin promote PI3K alpha/Akt signaling, and suggest how. The elevated calcium levels clinically observed in adenocarcinomas may explain calmodulin's involvement in recruiting and stimulating PI3K alpha through interaction with its n/cSH2 domains as well as K-Ras4B; importantly, it also explains why K-Ras4B specifically is a key player in ductal carcinomas, such as pancreatic (PDAC), colorectal (CRC), and lung cancers. We hypothesize that calmodulin recruits and helps activate PI3K alpha at the membrane, and that this is the likely reason for Ca2+/calmodulin dependence in adenocarcinomas. Calmodulin can contribute to initiation/progression of ductal cancers via both PI3K alpha/Akt and Raf/MEK/ERK pathways. Blocking the K-Ras4B/MAPK pathway and calmodulin/PI3Ka binding in a K-Ras4B/calmodulin/PI3K alpha trimer could be a promising adenocarcinoma-specific therapeutic strategy.Publication Metadata only The structural network of inflammation and cancer: merits and challenges(Academic Press Ltd- Elsevier Science Ltd, 2013) Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; The Center for Computational Biology and Bioinformatics (CCBB); Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745Inflammation, the first line of defense against pathogens can contribute to all phases of tumorigenesis, including tumor initiation, promotion and metastasis. Within this framework, the Toll-like receptor (TLR) pathway plays a central role in inflammation and cancer. Although extremely useful, the classical representation of this, and other pathways in the cellular network in terms of nodes (proteins) and edges (interactions) is incomplete. Structural pathways can help complete missing parts of such diagrams: they demonstrate in detail how signals coming from different upstream pathways merge and propagate downstream, how parallel pathways compensate each other in drug resistant mutants, how multi-subunit signaling complexes form and in particular why they are needed and how they work, how allosteric events can control these proteins and their pathways, and intricate details of feedback loops and how kick in. They can also explain the mechanisms of some oncogenic SNP mutations. Constructing structural pathways is a challenging task. Here, our goal is to provide an overview of inflammation and cancer from the structural standpoint, focusing on the TLR pathway. We use the powerful PRISM (PRotein Interactions by Structural Matching) tool to reveal important structural information of interactions in and within key orchestrators of the TLR pathway, such as MyD88.