Biography
Dr. Analisa DiFeo is an Associate Professor in the Department of Pathology and Obstetrics & Gynecology at the University of Michigan Medical School. She has over 17 years of experience in biomedical research focused on women’s cancers. She has a broad background in cancer genetics and biology, with specific training and expertise in miRNA biology, chemotherapy resistance, tumor initiation, and development of patient-based models. Her work spans the continuum translational research, beginning with an in-depth analysis of patient tumors and progressing to a functional assessment of key genetic drivers of ovarian cancer progression and the development of a novel therapeutic approach to abrogate these drivers to uncover therapies that will improve ovarian cancer patient survival. Furthermore, she has organized several translational research programs focused on ovarian cancer in New York and Cleveland. Currently, she is the Director of the Michigan Ovarian Cancer Science and Innovation Consortium (MOSAIC) which brings together passionate physicians, scientists, and patient advocates from diverse disciplines and several top research institutions in Michigan including University of Michigan, Michigan State, and Van Andel Institute to work together to perform impactful research that will uncover novel diagnostic tools for ovarian cancer and advanced stage uterine cancer. Through these programs she has developed a state-of-the-art gynecologic tumor biobank which includes novel patient-derived cell lines, organoids, and mouse models which are used to uncover advance personalized approaches to cancer treatment.
Her dedication to cancer research is evidenced by her accomplishments, which includes over 70 peer-reviewed publications and her ability to continuously secure numerous federal, foundation and industry-sponsored grants. She also serves on numerous grant review committees including as a Charter Member of Developmental Therapeutics at National Cancer Institute and a Standing Member on the Mission Boost Panel for the American Cancer Society. Additionally, she was chosen as Crain’s Cleveland Business 40 Under 40 honoree and received The Norma C. and Albert I. Geller Designated Professorship in Ovarian Cancer Research.
Beyond the aforementioned research, she also devotes considerable effort to training and mentoring future scientists, with the motto, "Pass your Passion”. She is the¬¬ Associate Director of the Cancer Biology Graduate Program and the Director of the Tumor Microenvironment: Impact on Cancer Biology and Response to Therapeutics” training grant at the University of Michigan. She has personally trained numerous clinical and basic scientists including Gynecologic Oncology Fellows, post-doctoral fellows, graduate students, medical students, undergraduates, high school students. Nearly all her trainees have established independent, successful careers in science in either academia or the pharmaceutical/ biotechnology industries and many have continued in the field of gynecological cancer research. She has also co-founded and serve as Chair of the Board of Scientific Advisors of The Young Scientist Foundation (YSF) (ysf.org) which aims to connect motivated high school students with biomedical scientists, to provide them with a unique opportunity to embark on careers in science by engaging in meaningful medical research. Ultimately, as an ovarian cancer translational scientist Dr. DiFeo is committed to performing impactful research that will improve the lives of women burdened by this disease through collaborative teamwork, rigorous research, and inspiring mentoring.
Research Interests
Our laboratory's work spans the translational research continuum, beginning with an in-depth analysis of patient tumors and progressing to a functional assessment of key genetic drivers of ovarian cancer progression and the development of a novel therapeutic approach to abrogate these drivers to uncover therapies that will improve ovarian cancer patient survival. To accomplish this, we focus on three major areas: 1) generation of clinically relevant gynecological cancer models, 2) discovery of potent genetic drivers with a focus on microRNAs involved in tumor initiation, drug resistance and recurrence, and 3) development of novel or re-purposed drugs.
1) Generation of clinically relevant gynecological cancer models.
Since the inception of the DiFeo lab, we have devoted a substantial amount of time to fostering collaborations with clinicians in order to build a well-integrated research program that would promote patient-focused, impactful research ideas and permit the development of a large repository of gynecologic tumors. Therefore, I have organized several translational research programs focused on gynecological cancer in New York, Cleveland, and Michigan. Currently, I am the Director of the Michigan Ovarian Cancer Science and Innovation Consortium (MOSAIC) and the co-PI of the gynecologic cancer tumor repository through these programs my laboratory has been able to collect over 500 advanced stage uterine and ovarian tumors. Most importantly, we have developed and fully characterized numerous patient-derived cell lines, organoids, and xenografts (PDX) which conserve original tumor characteristics such as heterogeneous histology, clinical biomolecular signature, malignant phenotypes and genotypes. Given that several studies have shown that many of the commercially available ovarian cancer cell lines do not recapitulate the genomic signature of patient tumors this resource has been used by investigators across the country. We have shared these models with numerous collaborators in the scientific community as well as licensed these models to various company's, which has led to the discovery of novel therapeutic targets, biomarkers, patent applications, and drugs. In addition, the DiFeo lab has established numerous sponsored research agreements with pharmaceutical company's to identify biomarkers and determine drug efficacy in ovarian and uterine PDX models.
2) Identifying functional drivers involved in ovarian cancer progression.
Our lab played a central role in defining KLF6 and its novel oncogenic splice variant, KLF6-SV1, as a key regulator of several human malignancies. Our findings were the first to demonstrate that the large majority of ovarian cancer tumors have increased expression of the oncogenic KLF6-SV1 isoform and high levels of this protein correlated with increased tumor aggressiveness. Furthermore, through these studies we discovered the KLF6-SV1 was a novel anti-apoptotic protein that targets the pro-survival molecule NOXA for degradation and its targeted inhibition extends survival ovarian cancer. These studies resulted in 18 publications during my doctoral and early post-doctoral studies in journal such as Science Translational Medicine, Journal of Clinical Investigation, Cancer Research, Clinical Cancer Research and Oncogene.
Currently, our laboratory is focused on uncovering functional microRNA:mRNA pathways driving ovarian cancer chemotherapy resistance and disease recurrence. We uncovered that microRNA-181a is a oncoMIR wherein it is frequently overexpressed in recurrent, platinum-resistant high-grade serous ovarian cancer (HGSC) and correlates with shorter time to recurrence and poor overall survival. Mechanistically, miR181a contributes to cellular transformation, metastasis initiation, and tumor recurrence by modulating chromosomal instability, EMT, and stemness factors via direct regulation of STING, TGFβ, and Wnt. Most recently, we have shown that in both immunodeficient and immunocompetent HGSC mouse models, targeted inhibition miR181a resulted in decreased tumor dissemination, ascites accumulation and increased sensitivity to immunotherapy. These studies have resulted in the numerous publications including two in Nature Communications. In addition, this research provides the rationale for determining whether pharmacological inhibition of miR181a can simultaneously inhibit the key signaling pathways implicated in cancer progression and significantly enhance patient survival. This work has resulted in the development of novel tools, such as a miR181a biosensor and a miR181a transgenic mouse, thereby laying the groundwork for future scientific endeavors and resources.
3) Development of novel or re-purposed drugs to treat platinum-resistant cancer.
The development of resistance to first-line chemotherapeutics most notably platinum-based therapies leaves few options for the clinical management of advanced ovarian cancer. Therefore, circumventing tumor resistance to commonly used first-line agents represents a very important aspect of multiple initiatives to eliminate ovarian cancer. Thus, another focus of our laboratory is to uncover the underlying mechanism of platinum resistance and to develop therapeutic strategies to treat recurrent, chemotherapy resistant disease. Through the development of numerous platinum resistant isogenic primary cell lines as well as patient-derived xenograft models we have uncovered several targetable pathways that can sensitize cells to platinum-based therapies. For example, we are the first to show that altered glutamine metabolism contributes to platinum resistant ovarian cancer and that targeting glutamine metabolism together with platinum-based chemotherapy offers a potential treatment strategy particularly in drug resistant ovarian cancer. Furthermore, we have recently found that small molecule mediated stabilization of protein phosphatase 2A (PP2A) modulates the Homologous Recombination pathway and potentiates DNA damage-induced cell death. These studies led to the discovery that PP2A modulators can surmount PARP inhibitor insensitivity, and that the combination of PP2A modulators and PARP inhibitors is a novel therapeutic approach for treating recurrent ovarian cancer. The findings from this research also culminated to a patent application, two grants from the Department of Defense, and a sponsored research agreement with Rappta Therapeutics, the company that licensed these drugs.
Research Opportunities for Rotating Students
1) development of novel or re-purposed drugs that can work alone or in conjunction with current treatment options to combat this deadly disease
2) discovery of potent drivers of drug resistance and recurrence
Diversity Ambassador
- First Generation College Student
Other Info
Office Location
- NCRC Building 520, Room 3345
Lab Location
- NCRC Building 520, Room 3345
Administrative Assistant
- Carrie Callahan
- Phone: 734-936-2499
- E-mail: [email protected]