Background: While we often think of ovarian cancer as an aggregate of cancer cells, in reality cancer cells are embedded in dense stroma which provides both structural scaffolding and gelatinous matrix that serves as a foundation of growth factors and nutrients necessary for cancer growth. At the same time, stroma shields cancer cells from normal immune recognition and physically limits the access of chemotherapies, anti-angiogenic therapies, and immunotherapies. Whereas in the past most therapeutic approaches have focused on the cancer cell, it is becoming apparent that the effects of anti¬cancer therapies could be significantly improved by simultaneously targeting of the cancer-protective stroma.
Problem: The main challenge in targeting cancer stroma is its similarity to normal stroma, which serves as a barrier to cancer metastasis and is necessary for the integrity of most human organs. To date there have been no effective methods to separate cancer-activated stroma from normal stroma. Experiments in animal models have shown that indiscriminate targeting of both types of stroma can actually promote cancer metastasis and cause serious damage to normal organs.
Proposed solution: Our laboratory has identified a protein called COL11A1 that is specifically expressed in cancer-activated stroma but not in normal stroma. We have also shown that high levels of COL11A1 are associated with ovarian cancer metastasis, recurrence, and poor patient survival. Our goals are to understand the roles of COL11A1 in stromal activation and cancer growth, and show the usefulness of COL11A1 as an anti-cancer target.
Research plan: We will study COL11A1 in ovarian cancer using a mouse model that was developed in our laboratory, and test whether targeting COL11A1 will greatly improve the effectiveness of anti-cancer therapy and prevent cancer growth. We will use genetic and immunology-based approaches to eliminate COL11A1 expression in cancer stroma in order to enhance chemotherapeutic accessibility to cancer cells and stop ovarian cancer growth.
Impact: Cancer-activated stroma promotes cancer progression and shields cancer cells from chemotherapy. Thus, simultaneous targeting of cancer stroma and cancer cells is necessary to achieve chemotherapeutic efficacy. COL11A1 is a particularly attractive therapeutic target because it is expressed in cancer-activated stroma but not in normal stroma. Testing COL11A1 as a precise target will be important for future anti-cancer drug development, to accurately and safely deliver drugs directly to cancer cells without damaging the normal stroma. In the clinical setting, this approach should lead to more effective and less toxic anti-cancer therapies.
Dongyu Jia, Ph.D., is currently a postdoctoral fellow with Dr. Sandra Orsulic in the Cedars-Sinai Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute (Los Angeles, CA). He obtained his Bachelor’s degree (2007) in Bioengineering at Chongqing University (China), where he received the Freshman Fellowship (2003) and Outstanding Student (2005-2007) awards. Under the supervision of Dr. Guixue Wang, his study focused on improving the performance of drug-eluting stents, and advanced the field by examining the efficacy of selected drugs on the reduction of restenosis, a recurrence of blood vessel narrowing after stent implantation. Later he joined the laboratory of Dr. Wu-Min Deng at Florida State University, where he received the Graduate Student Publication (2014) and Dissertation Research Grant (2015) awards, and earned his Ph.D. in Cellular and Molecular Biology (2015). His dissertation projects used the Drosophila egg chamber (fruit fly ovary) to understand Notch, JAK/STAT, and ecdysone signaling networks and their contribution to cell differentiation, proliferation, movement and cell fate determination, guiding the development of new treatments for human diseases caused by aberrant signaling activities. After joining Dr. Orsulic’s laboratory in 2015, Dr. Jia and collaborators discovered a COL11A1-correlated pan-cancer gene signature of activated fibroblasts that is conserved in epithelial cancers regardless of organ site and transforming events within cancer cells, which could be promising for the prioritization of therapeutic targets. Dr. Jia’s current efforts include functionally characterizing the roles of COL11A1 in stromal activation and promotion of ovarian cancer progression, and demonstrating the effectiveness of COL11A1 as a therapeutic target, using in vitro and nude mouse xenograft experiments.