Jill K. Slack-Davis
- PhD, State University of New York at Albany
- Assistant Professor, Microbiology, Immunology, and Cancer Biology
- Phone: 434-243-8579
- Email: jks6a@Virginia.EDU
Molecular Mechanisms Regulating Ovarian Cancer Metastasis
Ovarian cancer is the 4th leading cause of cancer related death among women, with an estimated 5-year survival of approximately 30-40%. The relatively poor prognosis is due largely to the advanced stage of disease at the time of diagnosis. Advanced stage tumors typically have peritoneal metastases along with ascites fluid accumulation. Treatment involves surgical resection followed by platinum/taxane-based chemotherapy. While this regimen results in a 75-80% clinical response rate, 50-75% of patients will have recurrent disease within 2-3 years. Clearly, there is a need for additional more effective therapeutics.
Ovarian carcinomas metastasize by attaching to and invading through the mesothelium, a layer of mesothelial cells that line the peritoneum and function in part to regulate fluid transport to and from underlying lymphatics. The ability of ovarian carcinoma cells to invade through the mesothelium is associated with a poor prognosis. We hypothesize that maintaining the barrier function of the mesothelium would stem progression of ovarian cancer by preventing tumor invasion and accumulation of ascites fluid. Furthermore, understanding the mechanisms that result in disruption of mesothelial integrity would provide additional sites for therapeutic intervention. Using cell culture and animal model systems, we identified the adhesion receptors VCAM-1 and VLA-4 (a4ß1 integrin) as regulators of ovarian cancer cell invasion and metastatic progression. Based on this foundation, the following projects have emerged:
- Regulation of mesothelial VCAM-1 expression in ovarian cancer
We demonstrated that VCAM-1 is preferentially expressed on the mesothelium of ovarian cancer patients compared to women with benign conditions. Building on this observation, we are exploring the mechanisms that regulate expression. Two regulators of VCAM-1 expression are found within the ascites of ovarian cancer patients, TNF-a and LPA. TNF-a is secreted by macrophages and ovarian cancer cells; LPA is produced by ovarian cancer cells and the mesothelium. Studies are designed to identify the relative contribution of the various cells to TNF-a and LPA production and the mechanisms by which these factors regulate mesothelial VCAM-1 expression.
- VLA-4 and chemoresponsiveness
One of the major obstacles to treating ovarian cancer is the development of platinum resistance. Indeed, 20% of patients are refractory to platinum based chemotherapy and many more will develop resistance. Using a mouse model of peritoneal ovarian cancer metastasis, we found that anti-VLA-4 antibody treatment renders tumors sensitive to platinum-based chemotherapy. We are currently investigating mechanistic basis for enhanced chemosensitivity following VLA-4 blockade.
- Scalici J, Harrer C, Allen A, Jazaeri A, Atkins K, McLachlan K, Slack-Davis J. Inhibition of α4β1 integrin increases ovarian cancer response to carboplatin. Gynecologic oncology. 2014;132(2): 455-61. PMID: 24378876
- Scalici J, Thomas S, Harrer C, Raines T, Curran J, Atkins K, Conaway M, Duska L, Kelly K, Slack-Davis J. Imaging VCAM-1 as an indicator of treatment efficacy in metastatic ovarian cancer. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2013;54(11): 1883-9. PMID: 24029657
- Stokes J, Adair S, Slack-Davis J, Walters D, Tilghman R, Hershey E, Lowrey B, Thomas K, Bouton A, Hwang R, Stelow E, Parsons J, Bauer T. Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Molecular cancer therapeutics. 2011;10(11): 2135-45. PMID: 21903606 | PMCID: PMC3213273
- Slack-Davis J, Dasilva J, Parsons S. LKB1 and Src: antagonistic regulators of tumor growth and metastasis. Cancer cell. 2010;17(6): 527-9. PMID: 20541695
- Tilghman R, Cowan C, Mih J, Koryakina Y, Gioeli D, Slack-Davis J, Blackman B, Tschumperlin D, Parsons J. Matrix rigidity regulates cancer cell growth and cellular phenotype. PloS one. 2010;5(9): e12905. PMID: 20886123 | PMCID: PMC2944843
- Slack-Davis J, Atkins K, Harrer C, Hershey E, Conaway M. Vascular cell adhesion molecule-1 is a regulator of ovarian cancer peritoneal metastasis. Cancer research. 2009;69(4): 1469-76. PMID: 19208843
- Slack-Davis J, Hershey E, Theodorescu D, Frierson H, Parsons J. Differential requirement for focal adhesion kinase signaling in cancer progression in the transgenic adenocarcinoma of mouse prostate model. Molecular cancer therapeutics. 2009;8(8): 2470-7. PMID: 19671741 | PMCID: PMC2728172
- Slack-Davis J, Martin K, Tilghman R, Iwanicki M, Ung E, Autry C, Luzzio M, Cooper B, Kath J, Roberts W, Parsons J. Cellular characterization of a novel focal adhesion kinase inhibitor. The Journal of biological chemistry. 2007;282(20): 14845-52. PMID: 17395594