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Postdoctoral Research Opportunity

Where: The University of Pennsylvania, Philadelphia, PA USA

Why study at the Penn Ovarian Cancer Research Center?

The University of Pennsylvania is the oldest and one of the finest medical schools in the United States. Penn is rich in tradition and heritage and at the same time consistently at the vanguard of new developments and innovations in medical education and research. Since its founding in 1765 the School has been a strong presence in the community and prides itself on educating the leaders of tomorrow in patient care, biomedical research, and medical education.

Founded in 2007, the Penn Ovarian Cancer Research Center (OCRC) has been a leader in cutting-edge research focused on gynecologic malignancies. The goal of the OCRC is to translate important biological principles discovered in the laboratory into clinically useful diagnostic and therapeutic tools. We achieve this goal through a multidisciplinary team approach that spans efforts in immunology and immunotherapy, vascular biology, epigenetics, genomics, early detection methods, and novel experimental model systems.

Dr. Ronny Drapkin is the Director of the Penn OCRC. The Drapkin laboratory focuses on a comprehensive understanding of the genetic, molecular and physiological factors that drive the development of high-grade serous ovarian carcinoma. Recent work from his group and others implicates the fallopian tube (FT) secretory cell as the likely cell-of-origin for a majority of high-grade serous ovarian carcinomas. The Drapkin laboratory has been at the forefront in developing novel experimental platforms that address the role of the FT epithelium and its susceptibility to neoplastic transformation. These platforms include genetically engineered mouse (GEM) models, fallopian tube-derived cell lines, and patient-derived xenografts.

Examples of current projects in the Drapkin laboratory:

  1. Molecular characterization of early and advanced FT lesions. We are using immunohistochemistry-coupled laser-capture microdissection to characterize early precancerous tubal lesions in BRCA mutation carriers vs non-BRCA patients using whole-exome sequence, DNA methylation, proteomics, and copy number analysis.
  2. Characterizing the PAX8 lineage-defining transcription factor. PAX8, a transcription factor which identifies nearly all ovarian cancers, is also the master regulator of FT development. RNA-Seq and ChiP-Seq studies indicate that the PAX8 cistrome is reprogrammed during neoplastic transformation. Ongoing studies are aimed at understanding its role at enhancer elements and the protein partners through which it functions.
  3. Defining the role of Cyclin E in early tubal precursor lesions. CCNE1 is amplified in 20% of high-grade serous carcinomas and is associated with poor overall survival. A gain-of-function screen has identified genes that cooperate with CCNE1 in the transformation of FT cells in vitro. A GEM model that targets the FT epithelium has also been developed to study the role of CCNE1 in vivo.
  4. Development of a tubal-derived cell line model for syngeneic studies. The dialog between the immune system and the cancer cell can dictate response to therapies, resistance mechanisms, and outcome. To study these interactions in a tractable model system, we have developed immortalized and CRISPR-Cas9 modified murine FT cells to determine how tumor genetics influences the immune response.
  5. Epigenetic histone modifications in tubal transformation. Monoubiquitination of histone H2B (H2Bub1) is an epigenetic mark known to regulate gene expression of distinct subsets of genes and plays a role in DNA repair. The E3 ligase responsible for H2Bub1, RNF20, is lost in half of all high-grade serous carcinomas. Ongoing studies show that H2Bub1 is lost early in human FT lesions and contributes to transformation by reprogramming inflammatory and metabolic pathways. Mechanistic studies are in progress.

Contact: rdrapkin@pennmedicine.upenn.edu