The DiFeo Lab
Departments of Pathology
and Obstetrics and Gynecology
The DiFeo lab is a well-integrated research program with a rich repository of patient-derived ovarian and endometrial cancer models that are highly useful for translational research and is perfectly poised to perform impactful research to detect these cancers earlier and treat them more effectively.
The work performed in our laboratory spans the continuum of translational research starting with an in-depth analysis of patient samples to functional assessment of key genetic drivers of ovarian cancer progression to the development of a novel early detection biomarkers and therapeutic approaches to abrogate these drivers in order to improve ovarian cancer patient survival.
What we do
The overall goal of my laboratory is to identify the alterations that lead to gynecological cancers, specifically high serous cancer (HGSC), the most common subtype of ovarian cancer in order to develop novel biomarkers and therapies.
In order to accomplish this, we focus on four major areas: 1) generation of clinically relevant mouse models, 2) development of novel or re-purposed drugs that can combat this deadly disease, 3) discovery of potent drivers of drug resistance and recurrence, and 4) identify novel biomarkers for early detection or therapeutic response.
A major focus of the lab is determining the mechanism tumor recurrence and chemotherapy resistance. We uncovered that microRNA-181a is frequently overexpressed in recurrent, platinum-resistant tumors and correlates with shorter time to recurrence and poor overall survival. Functionally, we found that is a potent oncomiR because it is 1) highly expressed in a large majority of cancers; 2) correlates with poor patient outcome; and 3) drives tumor-initiation and recurrence through the regulation of potent cancer signaling pathways such as TGFβ, Wnt, through the potent inhibition of the Stimulator of Interferon Genes (STING), which promotes the growth of highly aggressive and genomically unstable cells. Most importantly, we found that miR-181a expression negatively correlated with STING expression in high-grade serous ovarian cancer (HGSC) patient tumors, which in turn resulted in decreased tumor immune activation and interferon-gamma immune score. Given the lack of miRNA targeting drugs in oncology we have also developed a novel microRNA (miRNA) sensor platform that represents a reliable and successful approach to finding small molecule inhibitors of miRNA function that can significantly enhance the translational potential of miRNA therapeutics in both cancers and physiological contexts.
Furthermore, in order to ensure clinical translation of our findings my lab has built a well-integrated research program which includes a rich repository of patient tumors, that are highly useful for translational research. Through this program we developed an extensive gynecologic tumor biobank which includes novel patient-derived cell lines and mouse xenografts (PDX) which we have been able to utilize to uncover numerous molecular factors that are involved in HGSC biology and the development of chemotherapy resistance as well as validate the efficacy of several novel and re-purposed drugs.
