Ioannis Zervantonakis, PhD

Assistant Professor

UPMC Hillman Cancer Center

Center for Bioengineering | 300 Technology Drive | Pittsburgh, PA 15219

ioz1@pitt.edu www.zervalab.org

Tumor Microenvironment Engineering Laboratory

Understanding cell behavior in native tumor microenvironments and developing new strategies to deliver therapeutics directly to tumor cells are critical in improving and extending patients’ lives. Our lab employs a quantitative approach that integrates microfluidics, systems biology modeling, and in vivo experiments to investigate the role of the tumor microenvironment on breast and ovarian cancer growth, metastasis and drug resistance. Our goal is to develop bioengineered tumor microenvironment platforms and apply them to improve understanding of tumor-stromal signaling mechanisms in order to: (1) discover biomarkers that guide new drug development and improve prognosis, (2) develop new strategies to improve existing treatment protocols and (3) engineer microfabricated tools that enable screening and personalization of cancer therapies.

Research Projects

1. Cellular dynamics in stroma-rich breast cancer microenvironments

Advanced HER2+ breast cancer has a poor prognosis; improving patient outcomes will depend on elucidating mechanisms of therapy resistance. Motivated by our in vitro coculture studies, we hypothesized that fibroblasts activate tumor cell pro-survival signaling and contribute to drug resistance. To dissect mechanisms of fibroblast-mediated therapy resistance we measure the dynamics of breast cancer cells to HER2-targeting therapy using microfluidic tumor slice cultures and controlled co-culture assays. By integrating live cell death measurements with mathematical modeling we explore mechanisms of cell-cell communication and develop an integrative framework to predict therapy resistance in breast tumors that exhibit different stromal fibroblast densities.

2. Microfluidic models of ovarian cancer metastasis

Ovarian cancer is oftentimes not detected until after metastases have occurred. The mechanisms of tumor cell survival during metastatic spread and the role of biomechanical and biochemical factors on ovarian cancer invasion remain poorly understood. We have developed a microfluidic device to control the interactions of ovarian cancer cells with a mesothelial barrier and macrophages under fluid flow. The goal of this project is to determine the role of fluid flow-induced forces and biochemical factors secreted by macrophages on ovarian cancer invasion.

3. Localized drug release and single-cell technologies in cancer therapies

We have developed a 3D acoustofluidic platform to monitor heating-induced localized drug release and study mechanisms of thermal cytotoxic therapy enhancement in invasive ovarian cancer. To improve therapies targeting heterogeneous ovarian cancers we are engineering single-cell microwell assays that enable screening of patient-derived cells and xenograft models.