Ioannis Zervantonakis

Ioannis Zervantonakis
University of Pittsburgh | Pitt · Bioengineering

Assistant Professor in Bioengineering

About

127
Publications
36,775
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
4,008
Citations
Citations since 2016
72 Research Items
2926 Citations
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500
Introduction
Assistant Professor, Department of Bioengineering and Hillman Cancer Center, University of Pittsburgh. Our lab is growing, opportunities for new members to join. Please contact me and visit my lab website for more information: http://www.zervalab.com
Additional affiliations
September 2019 - present
University of Pittsburgh
Position
  • Professor (Assistant)
February 2013 - August 2019
Harvard University
Position
  • PostDoc Position
August 2007 - December 2012
Massachusetts Institute of Technology
Position
  • PhD Student
Education
September 2007 - November 2012
Massachusetts Institute of Technology
Field of study
  • Bioengineering

Publications

Publications (127)
Article
Full-text available
The majority of patients with high grade serous ovarian cancer (HGSOC) develop recurrent disease and chemotherapy resistance. To identify drug combinations that would be effective in treatment of chemotherapy resistant disease, we examined the efficacy of drug combinations that target the three antiapoptotic proteins most commonly expressed in HGSO...
Article
Full-text available
We are rapidly approaching a future in which cancer patient digital twins will reach their potential to predict cancer prevention, diagnosis, and treatment in individual patients. This will be realized based on advances in high performance computing, computational modeling, and an expanding repertoire of observational data across multiple scales an...
Article
INTRODUCTION: One of the most fundamental problems that oncologists are currently facing in pancreatic cancer patient care is the high resistance to all types of chemotherapies or targeted therapies. Thus, there is an urgent need for increasing patient response to treatment. A common characteristic among most pancreatic cancer patients that could s...
Article
Full-text available
Theevolutionofbreasttumorsgreatlydependsontheinteractionnetworkamongdifferent cell types, including immune cells and cancer cells in the tumor. This study takes advantage of newly collected rich spatio-temporal mouse data to develop a data-driven mathematical model of breast tumors that considers cells’ location and key interactions in the tumor. T...
Article
Full-text available
The most common kind of cancer among women is breast cancer. Understanding the tumor microenvironment and the interactions between individual cells and cytokines assists us in arriving at more effective treatments. Here, we develop a data-driven mathematical model to investigate the dynamics of key cell types and cytokines involved in breast cancer...
Article
Normal cells explore multiple states to survive stresses encountered during development and self-renewal as well as environmental stresses such as starvation, DNA damage, toxins or infection. Cancer cells co-opt normal stress mitigation pathways to survive stresses that accompany tumour initiation, progression, metastasis and immune evasion. Cancer...
Article
Full-text available
Advanced or metastatic pancreatic cancer is highly resistant to existing therapies, and new treatments are urgently needed to improve patient outcomes. Current studies focus on alternative treatment approaches that target the abnormal microenvironment of pancreatic tumors and the resulting elevated mechanical stress in the tumor interior. Neverthel...
Article
Full-text available
Breast cancer is the most prominent type of cancer among women. Understanding the microenvironment of breast cancer and the interactions between cells and cytokines will lead to better treatment approaches for patients. In this study, we developed a data-driven mathematical model to investigate the dynamics of key cells and cytokines involved in br...
Article
Full-text available
Intercellular mechanisms by which the stromal microenvironment contributes to solid tumor progression and targeted therapy resistance remain poorly understood, presenting significant clinical hurdles. PEAK1 (Pseudopodium-Enriched Atypical Kinase One) is an actin cytoskeleton-and focal adhesion-associated pseudokinase that promotes cell state plasti...
Preprint
Full-text available
New treatments for patients with advanced or metastatic pancreatic cancers are urgently needed due to their resistance to all current therapies. Current studies focus on alternative treatment approaches that target or normalize the abnormal microenvironment of pancreatic tumors, which among others, is responsible for elevated mechanical stress in t...
Article
In ovarian cancer, the presence of macrophages in the tumor microenvironment (TME) has been associated with poor clinical outcomes. Understanding mechanisms of macrophage recruitment and signaling with tumor cells in the TME may uncover novel therapeutic targets to block the pro-tumor effects of macrophages and improve patient outcomes. Several tum...
Article
Perturbation biology is a powerful approach to modeling quantitative cellular behaviors and understanding detailed disease mechanisms. However, large-scale protein response resources of cancer cell lines to perturbations are not available, resulting in a critical knowledge gap. Here we generated and compiled perturbed expression profiles of ∼210 cl...
Article
The ratio of two cancer-associated fibroblast subpopulations with distinct functions affects breast cancer clinical outcomes.
Article
Full-text available
Cancer cells have genetic alterations that often directly affect intracellular protein signaling processes allowing them to bypass control mechanisms for cell death, growth and division. Cancer drugs targeting these alterations often work initially, but resistance is common. Combinations of targeted drugs may overcome or prevent resistance, but the...
Preprint
Full-text available
Perturbation biology is a powerful approach to developing quantitative models of cellular behaviors and gaining mechanistic insights into disease development. In recent years, large-scale resources for phenotypic and mRNA responses of cancer cell lines to perturbations have been generated. However, similar large-scale protein response resources are...
Article
Full-text available
Significance Factors stemming from the tumor microenvironment can modulate drug resistance. Therefore, rational approaches to design efficacious targeted therapies are needed. Here, we show that fibroblasts reduce lapatinib sensitivity in a subset of HER2 ⁺ breast cancer cells via paracrine signaling that can be reversed by targeting downstream sur...
Article
The extent of lymphocyte infiltration controls cancer subclone divergence, and a single immune cold region can increase the risk of relapse.
Preprint
Full-text available
Intercellular mechanisms by which the stromal microenvironment contributes to solid tumor progression and targeted therapy resistance remain poorly understood, presenting significant clinical hurdles. PEAK1 (Pseudopodium-Enriched Atypical Kinase One) is an actin cytoskeleton- and focal adhesion-associated pseudokinase that promotes cell state plast...
Article
Sequential treatment provides therapeutic benefit in pancreatic cancer models.
Article
Human bone-marrow-on-a-chip improves drug studies of hematopoietic cell function and identifies a neutrophil maturation defect in a genetic disorder.
Article
Full-text available
Prediction 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 acr...
Article
Nanoparticle surface chemistry is a fundamental engineering parameter that governs tumor-targeting activity. Electrostatic assembly generates controlled polyelectrolyte complexes through the process of adsorption and charge overcompensation utilizing synthetic polyions and natural biomacromolecules; it can yield films with distinctive hydration, ch...
Conference Paper
*Co-senior authors Primary high-grade serous ovarian cancer (HGSOC) is often sensitive to platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. Although alterations in DNA repair function, gene expression, apoptosis, and other pathways have been described that can mediate chemotherapy resistanc...
Article
High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplati...
Preprint
Full-text available
Data-driven mathematical modeling of biological systems has enormous potential to understand and predict the interplay between molecular and phenotypic response to perturbation, and provides a rational approach to the nomination of therapies in complex diseases such as cancer. Melanoma is a particularly debilitating disease for which most therapies...
Article
Background: Inflammatory Breast Cancer (IBC) is an aggressive subtype of breast cancer that is associated with an increased likelihood of early metastasis and a poor prognosis, accounting for approximately 10% of all breast cancer mortality. Currently, there is limited availability of cell line and patient-derived xenograft (PDX) models of IBC. As...
Article
p>Most patients with late stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC making it an attractive therapeutic target. Here, we systematical...
Preprint
Full-text available
Non-small-cell lung cancer is the leading cause of cancer death worldwide. Although radiotherapy is an effective treatment choice for early-stage cases, the 5-year survival rate of patients diagnosed in late-stages remains poor. Increasing evidence suggests that the local and systemic effects of radiotherapy dependent on the induced anti-tumor immu...
Article
Full-text available
Necroptosis is a lytic programmed cell death mediated by the RIPK1-RIPK3-MLKL pathway. The loss of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) expression and necroptotic potential have been previously reported in several cancer cell lines; however, the extent of this loss across cancer types, as well as its mutational drivers, we...
Data
AXL/TYRO3 expression correlation with expression of RIPK3 versus other necroptosis-related genes. (A) Pearson correlation analysis using CCLE mRNA expression database for known necroptosis-related proteins was performed and a heatmap for the Pearson coefficients was generated using ClustVis. (B) High AXL expression positively correlates with low RI...
Data
AXL/TYRO3 expression correlation with expression of RIPK3 and TSZ-IC50 values. (A) High AXL expression positively correlates with resistance to TSZ-induced necroptosis. Pearson correlation analysis for AXL mRNA levels versus TSZ-IC50 values for the screened cancer cell lines. Markers stacked at IC50 = 1 value indicate cell lines with no response to...
Data
Mutational enrichment analysis for NR-RIPK3high cell lines. (A) A total of 75 of the NR cell lines have not lost RIPK3 expression (RIPK3high). RIPK3high subpopulation was defined as cell lines with RIPK3 expression greater than the third quartile of the 941-cell-line population. NR subpopulation was defined as cell lines that showed no cell death a...
Data
(A) Loss of RIPK3 expression during tumorigenesis. RIPK3 expression is progressively lost during tumorigenesis. Ovarian PDX lysates obtained at the indicated in vivo passages were immunoblotted with the indicated antibodies. The lack of RIPK3 expression loss in all of the PDX samples highlights the heterogeneity of this event in cancer. (B) Effect...
Data
Excel file containing the underlying numerical data for Figs 1A, 1B, 1C, 1E, 1F, 2B, 2E, 2F, 3A, 3B, 3C, 3D, 3E, 3F, 4A, 4B, 4C, 4D, 4E, 4F, S1B, S1C, S2A, S2B, S2C, S3B, S4B, S5A, S5B, S5C, S5D, S6A, S6B and S7. Data are given in indicated separate sheets. (XLSX)
Data
Necroptosis sensitivity screen confirmation by TCZ treatment and distribution of the cell lines in the screen across tissue types. (A) Low-throughput confirmation of the screen observations regarding necroptosis resistance. Indicated cells were treated with TCZ (TNFα = 20 ng/mL; CHX = 0.5 μg/mL, 30-minute pretreatment; zVAD = 25 μM, 30-minute pretr...
Data
High-throughput screening data analysis strategy and enrichment of low RIPK3 expression levels in necroptosis-resistant cell lines. (A) Outline of the data analysis strategy for differential necroptosis sensitivity data from the cell-based high-throughput screen described in Fig 1 that identified 20 oncogene-related genes that correlate with high n...
Data
High AXL expression positively correlates with low RIPK3 expression levels in cell lines with wild-type BRAF, and this correlation is decreased in cell lines with mutant BRAF. Pearson p-values were used for the analysis. The underlying data can be found in S1 Data. (TIF)
Article
The cellular and molecular heterogeneity of solid tumors, like breast cancer, is a significant hurdle in the effort to develop effective therapies. The complex breast cancer microenvironment (BCME) includes mesenchymal stromal cells (MSCs) that engage in paracrine/juxtacrine signaling with adjacent tumor cells to support disease progression. Since...
Article
Full-text available
The 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 vulne...
Article
High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths. Despite an initial response to platinum-based chemotherapy, treatment resistance eventually occurs in most patients. The overall aim of our studies is to identify synergistic drug combinations for the treatment of HGSOC and biomarkers that predict sensitivity for...
Article
Endothelial permeability has been extensively investigated in the context of pathologies such as cancer and also in studies of drug delivery from the circulation. Hypoxia is a critical regulator of endothelial cell (EC) behavior and affects the barrier function of endothelial linings, yet its role has been little studied. This paper reveals the eff...
Article
Despite recent advances in understanding the biology of ovarian tumors and the development of targeted therapies, primary or acquired resistance to therapy remains the major cause of treatment failure. Improvements in “omics” measurement technologies offer new opportunities for cancer systems biology approaches to model and predict drug resistance....
Article
Full-text available
Purpose: Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States, with high rates of recurrence and eventual resistance to cytotoxic chemotherapy. Model systems that allow for accurate and reproducible target discovery and validation are needed to support further drug development in this disease. Experimental...
Article
HER2-targeting antibodies (i.e. trastuzumab and pertuzumab) prolong survival in HER2-positive breast cancer patients with extracranial metastases. However, the response of brain metastases to these drugs is poor, and it is hypothesized that the blood-brain barrier (BBB) limits drug delivery to the brain. We investigated whether we could improve the...
Article
Full-text available
Despite advances in understanding the genetics and molecular biology of high grade serous ovarian cancer, there have not been any significant improvements in the outcome of patients treated with approved therapies to date. The overall aim of our studies is to identify synergistic drug combinations for the treatment of high-grade serous ovarian (HGS...
Article
Full-text available
High-grade serous ovarian carcinoma (HGS-OvCa) harbors p53 mutations and can originate from the epithelial cell compartment of the fallopian tube fimbriae. From this site, neoplastic cells detach, survive in the peritoneal cavity, and form cellular clusters that intercalate into the mesothelium to form ovarian and peritoneal masses. To examine the...
Article
Full-text available
Cell-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 co...
Article
Unlabelled: Immune cells promote the initial metastatic dissemination of carcinoma cells from primary tumors. In contrast to their well-studied functions in the initial stages of metastasis, the specific roles of immunocytes in facilitating progression through the critical later steps of the invasion-metastasis cascade remain poorly understood. He...
Article
Overcoming transport barriers to delivery of therapeutic agents in tumors remains a major challenge. Focused ultrasound (FUS), in combination with modern nanomedicine drug formulations, offers the ability to maximize drug transport to tumor tissue while minimizing toxicity to normal tissue. This potential remains unfulfilled due to the limitations...
Article
Despite advances in understanding the genetics and molecular biology of high grade serous ovarian cancer, there have not been any significant improvements in the outcome of patients treated with approved therapies to date. The overall aim of our studies is to identify synergistic drug combinations for the treatment of high-grade serous ovarian (HGS...