Ovarian cancer is the most lethal gynecological malignancy and is the 5th most frequent cause of cancer-related deaths among women in the US. Nearly 70% of women are diagnosed with advanced, incurable stages of the disease. Efforts to better treat ovarian cancer hinge upon having an accurate understanding of the cellular, molecular and genetic events leading to the disease. Recent extensive studies of a large number of the most common and aggressive type of ovarian cancer, high-grade serous carcinoma (HGSOC), have described a broad repertoire of genomic alterations common for this disease. Unfortunately, practical utilization of this information is hindered because the originating cells are not established. While some investigators contend that malignancies originate from the ovarian surface epithelium (OSE), others believe that they originate from the tubal (Fallopian) epithelium (TE). Recently we have discovered stem cell niches located at the junctions between OSE, mesothelium and TE. We have also shown that HGSOC may preferentially originate from these stem cell niches. However, some cancers may also arise from more differentiated cells. It is unknown if the cell of origin may pre-program biological behavior of ovarian cancer. Furthermore, it is also unclear if the development of different types of ovarian carcinomas, such as high and low grade serous and endometrioid carcinomas, depends on the transformation of cells at a particular stage of their differentiation.
We plan to address these questions by joint efforts of laboratories at Cornell University and Weill Cornell Medical College. The PIs of these laboratories have long-standing interest in cancer research and reproductive biology. The combination of their unique expertise in ovarian cancer research (Drs. Nikitin and Ellenson), stem cell biology (Dr. Nikitin), genomics (Dr. Schimenti) and surgical and comparative pathology (Drs. Nikitin and Ellenson) enables a synergistic interaction and multidisciplinary approach to the problem. The research team has a track record of previous successful collaborations and operates in a highly supportive institutional environment. We expect that our research will significantly improve our understanding of ovarian carcinoma pathogenesis and lead to identification of early critical drivers of this malignancy. Our findings also will stimulate targeted searches for preneoplastic/early neoplastic lesions in the areas of transition between OSE, mesothelium and TE in humans. Successful development of this project is expected to lay the basis for translational studies, such as identification of unique biomarkers and therapeutic targets based on stratification of ovarian carcinoma according to their cell of origin and causative genetic alterations. The funding of the current proposal will provide us with the necessary leverage to compete successfully for an NCI or DOD funded program project grant.
This grant was made possible in part by a generous donation from the Randall and Barbara Smith Foundation.
- Lora Hedrick Ellenson, MD, Cornell University
- John Schimenti, PhD, Cornell University
Alexander Nikitin, M.D., Ph.D. is Professor of Pathology in the Department of Biomedical Sciences and Leader of the Cornell Stem Cell Program at the Cornell University. He is also Director of the Cornell Stem Cell Pathology Unit and is Co-Director of the Cornell Stem Cell Modeling and Phenotyping Core. Dr. Nikitin earned his M.D. (with Distinction) from the Pavlov First Medical Institute and Ph.D. in Pathology from the Petrov Research Institute of Oncology, both in St. Petersburg, Russia. After work as a diagnostic pathologist in the Petrov Research Institute of Oncology, St. Petersburg Russia, he performed postdoctoral and junior faculty research at the University of Essen Medical School in Germany and at the University of Texas Health Science Center at San Antonio in Texas. Dr. Nikitin joined the Cornell University faculty in 2000.
Dr. Nikitin’s research aims to understand how aberrations in molecular and cellular mechanisms governing the tissue homeostasis may lead to cancer initiation and progression. He has over 25 years of experience in cancer research, with ovarian cancer studies being one of the most significant parts of his activities during past 14 years. In that area, his laboratory established the first autochthonous mouse model of high-grade serous ovarian carcinoma, identified transcriptional regulation of genes encoding miR-34 family by p53, reported common downregulation of mir-34 genes in ovarian cancer, showed the importance of feed-forward p53/miR-34/MET loop for the control of cell motility and invasion, and identified a novel cancer-prone niche in the ovarian surface epithelium. Dr. Nikitin’s research is complemented by cross-disciplinary collaborations in technology-oriented areas, such as nonlinear microscopy, intravital imaging and nanotechnology.