Person: Zervantonakis, Ioannis
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Zervantonakis
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Ioannis
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Zervantonakis, Ioannis
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Publication A Large Peptidome Dataset Improves HLA Class I Epitope Prediction Across Most of the Human Population(Nature, 2019-12-16) Le, Phuong M; Li, Letitia W; Oliveira, Giacomo; Keshishian, Hasmik; Hartigan, Christina R; Zhang, Wandi; Bachireddy, Pavan; Ouspenskaia, Tamara; Law, Travis; Justesen, Sune; Stevens, Jonathan; Eisenhaure, Thomas; Zhang, Guang Lan; Klauser, Karl R; Hacohen, Nir; Carr, Steven A; Sarkizova, Siranush; Klaeger, Susan; Braun, David; Ligon, Keith; Zervantonakis, Ioannis; Rosenbluth, Jennifer; Lane, William; Wu, Catherine; Keskin, DerinPrediction of HLA epitopes is important for the development of cancer immunotherapies and vaccines. However, current prediction algorithms have limited predictive power, in part because they were not trained on high-quality epitope datasets covering a broad range of HLA alleles. To enable prediction of endogenous HLA class I–associated peptides across a large fraction of the human population, we used mass spectrometry to profile >185,000 peptides eluted from 95 HLA-A, B, C and G mono-allelic cell lines. We identified canonical peptide motifs per HLA allele, unique and shared binding submotifs across alleles, and distinct motifs associated with different peptide lengths. By integrating these data with transcript abundance and peptide processing, we developed HLAthena, providing allele-and-length-specific and pan-allele-pan-length prediction models for endogenous peptide presentation. These models predicted endogenous HLA class I–associated ligands with 1.5-fold improvement in positive predictive value compared with existing tools and correctly identified >75% of HLA-bound peptides that were observed experimentally in 11 patient-derived tumor cell lines.Publication Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response(Nature Publishing Group UK, 2017) Zervantonakis, Ioannis; Iavarone, Claudia; Chen, Hsing-Yu; Selfors, Laura; Palakurthi, Sangeetha; Liu, Joyce F.; Drapkin, Ronny; Matulonis, Ursula; Leverson, Joel D.; Sampath, Deepak; Mills, Gordon B.; Brugge, JoanThe lack of effective chemotherapies for high-grade serous ovarian cancers (HGS-OvCa) has motivated a search for alternative treatment strategies. Here, we present an unbiased systems-approach to interrogate a panel of 14 well-annotated HGS-OvCa patient-derived xenografts for sensitivity to PI3K and PI3K/mTOR inhibitors and uncover cell death vulnerabilities. Proteomic analysis reveals that PI3K/mTOR inhibition in HGS-OvCa patient-derived xenografts induces both pro-apoptotic and anti-apoptotic signaling responses that limit cell killing, but also primes cells for inhibitors of anti-apoptotic proteins. In-depth quantitative analysis of BCL-2 family proteins and other apoptotic regulators, together with computational modeling and selective anti-apoptotic protein inhibitors, uncovers new mechanistic details about apoptotic regulators that are predictive of drug sensitivity (BIM, caspase-3, BCL-XL) and resistance (MCL-1, XIAP). Our systems-approach presents a strategy for systematic analysis of the mechanisms that limit effective tumor cell killing and the identification of apoptotic vulnerabilities to overcome drug resistance in ovarian and other cancers.Publication Synergistic Effects of 3D ECM and Chemogradients on Neurite Outgrowth and Guidance: A Simple Modeling and Microfluidic Framework(Public Library of Science, 2014) Srinivasan, Parthasarathy; Zervantonakis, Ioannis; Kothapalli, Chandrasekhar R.During nervous system development, numerous cues within the extracellular matrix microenvironment (ECM) guide the growing neurites along specific pathways to reach their intended targets. Neurite motility is controlled by extracellular signal sensing through the growth cone at the neurite tip, including chemoattractive and repulsive cues. However, it is difficult to regenerate and restore neurite tracts, lost or degraded due to an injury or disease, in the adult central nervous system. Thus, it is important to evaluate the dynamic interplay between ECM and the concentration gradients of these cues, which would elicit robust neuritogenesis. Such information is critical in understanding the processes involved in developmental biology, and in developing high-fidelity neurite regenerative strategies post-injury, and in drug discovery and targeted therapeutics for neurodegenerative conditions. Here, we quantitatively investigated this relationship using a combination of mathematical modeling and in vitro experiments, and determined the synergistic role of guidance cues and ECM on neurite outgrowth and turning. Using a biomimetic microfluidic system, we have shown that cortical neurite outgrowth and turning under chemogradients (IGF-1 or BDNF) within 3D scaffolds is highly regulated by the source concentration of the guidance cue and the physical characteristics of the scaffold. A mechanistic-driven partial differential equation model of neurite outgrowth has been proposed, which could also be used prospectively as a predictive tool. The parameters for the chemotaxis term in the model are determined from the experimental data using our microfluidic assay. Resulting model simulations demonstrate how neurite outgrowth was critically influenced by the experimental variables, which was further supported by experimental data on cell-surface-receptor expressions. The model results are in excellent agreement with the experimental findings. This integrated approach represents a framework for further elucidation of biological mechanisms underlying neuronal responses of specialized cell types, during various stages of development, and under healthy or diseased conditions.Publication Registered report: Discovery and preclinical validation of drug indications using compendia of public gene expression data(eLife Sciences Publications, Ltd, 2015) Kandela, Irawati; Zervantonakis, IoannisThe Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of 50 papers in the field of cancer biology published between 2010 and 2012. This Registered report describes the proposed replication plan of key experiments from ‘Discovery and Preclinical Validation of Drug Indications Using Compendia of Public Gene Expression Data’ by Sirota et al., published in Science Translational Medicine in 2011 (Sirota et al., 2011). The key experiments being replicated include Figure 4C and D and Supplemental Figure 1. In these figures, Sirota and colleagues. tested a proof of concept experiment validating their prediction that cimetidine, a histamine-2 (H2) receptor agonist commonly used to treat peptic ulcers (Kubecova et al., 2011), would be effective against lung adenocarcinoma (Figure 4C and D). As a control they also tested the effects of cimetidine against renal carcinoma, for which it was not predicted to be efficacious (Supplemental Figure 1). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife. DOI: http://dx.doi.org/10.7554/eLife.06847.001Publication A protein interaction map for cell-cell adhesion regulators identifies DUSP23 as a novel phosphatase for β-catenin(Nature Publishing Group, 2016) Gallegos, Lisa Leon; Ng, Mei Rosa; Sowa, Mathew E.; Selfors, Laura; White, Anne; Zervantonakis, Ioannis; Singh, Pragya; Dhakal, Sabin; Harper, J. Wade; Brugge, JoanCell-cell adhesion is central to morphogenesis and maintenance of epithelial cell state. We previously identified 27 candidate cell-cell adhesion regulatory proteins (CCARPs) whose down-regulation disrupts epithelial cell-cell adhesion during collective migration. Using a protein interaction mapping strategy, we found that 18 CCARPs link to core components of adherens junctions or desmosomes. We further mapped linkages between the CCARPs and other known cell-cell adhesion proteins, including hits from recent screens uncovering novel components of E-cadherin adhesions. Mechanistic studies of one novel CCARP which links to multiple cell-cell adhesion proteins, the phosphatase DUSP23, revealed that it promotes dephosphorylation of β-catenin at Tyr 142 and enhances the interaction between α- and β-catenin. DUSP23 knockdown specifically diminished adhesion to E-cadherin without altering adhesion to fibronectin matrix proteins. Furthermore, DUSP23 knockdown produced “zipper-like” cell-cell adhesions, caused defects in transmission of polarization cues, and reduced coordination during collective migration. Thus, this study identifies multiple novel connections between proteins that regulate cell-cell interactions and provides evidence for a previously unrecognized role for DUSP23 in regulating E-cadherin adherens junctions through promoting the dephosphorylation of β-catenin.Publication Controlled electromechanical cell stimulation on-a-chip(Nature Publishing Group, 2015) Pavesi, Andrea; Adriani, Giulia; Rasponi, Marco; Zervantonakis, Ioannis; Fiore, Gianfranco B.; Kamm, Roger D.Stem cell research has yielded promising advances in regenerative medicine, but standard assays generally lack the ability to combine different cell stimulations with rapid sample processing and precise fluid control. In this work, we describe the design and fabrication of a micro-scale cell stimulator capable of simultaneously providing mechanical, electrical, and biochemical stimulation, and subsequently extracting detailed morphological and gene-expression analysis on the cellular response. This micro-device offers the opportunity to overcome previous limitations and recreate critical elements of the in vivo microenvironment in order to investigate cellular responses to three different stimulations. The platform was validated in experiments using human bone marrow mesenchymal stem cells. These experiments demonstrated the ability for inducing changes in cell morphology, cytoskeletal fiber orientation and changes in gene expression under physiological stimuli. This novel bioengineering approach can be readily applied to various studies, especially in the fields of stem cell biology and regenerative medicine.