Identifying the microenvironmental interactions that regulate cancer metastasis is key to controlling this disease. We have shown that immune cell-containing structures, known as milky spots in the omentum are required for ovarian cancer colonization of peritoneal adipose. Organ-specific colonization might be governed in part by interactions between chemokine receptors on cancer cells and chemokine gradients in target organs. Chemokine receptors are expressed on tumor cells and play a role in directing metastasis to secondary organs (1-3). We have identified specific immune cells known as macrophages as the key mediators of colonization. Specifically, we have identified macrophage-secreted protein CCL6 (CCL15 in humans) and its corresponding receptor, CCR1, as a key chemokine axis that ovarian cancer cells use to selectively infiltrate the omentum. CCR1 is the only CC chemokine receptor that is consistently detected in solid ovarian tumors (75% of patients).
Based on these findings, we hypothesize that activation the receptor, CCR1, by omental macrophage-secreted CCL6/CCL15 promotes early colonization of ovarian cancer cells.
Specific Aim 1 will determine the impact of omental macrophage-derived CCL6 on cancer recruitment. Specific Aim 2 will determine the role of CCR1 in ovarian cancer cell homing to the omentum.
In the short-term, studies herein will provide the first mechanistic information on 1) the molecular pathways activated in milky spot macrophages that promote localization of precursor cells to the omentum. In the long term, we hope to provide defined, therapeutic targets for prevention of high grade serous ovarian cancer (HGSC). Our project will identify cancer cell-macrophage interactions that can be targeted therapeutically to disrupt metastatic growth and extend disease-free survival.
Our proposed work is, to our knowledge, the first to clarify how the omental microenvironment contributes to the development of HGSC in both experimental models and clinical disease. Our multi-disciplinary team of basic and translational researchers, immunologists, bioinformaticians, and pathologists will allow us to develop strategic therapeutic interventions that target precursor lesions and the microenvironment. Currently we lack effective prevention strategies for HGSC, especially in patients at high-risk for disease (BRCA mutation carriers). These individuals would be immediate candidates for therapies that could prevent or control the growth of disseminated precursor cells if such therapies existed.
This grant was made possible in part through the generous donation of Tell Every Amazing Lady About Ovarian Cancer Louisa McGregor Ovarian Cancer Foundation, also known as T.E.A.L.®
Dr. Krishnan is currently an Instructor at the Department of Obstetrics and Gynecology at Stanford University. Dr. Krishnan has identified a key role for adipose tissue macrophages in ovarian cancer colonization of the omentum. His research interests are focused on defining the mechanism(s) by which the omental microenvironment supports and promotes progression of precursor cells to high-grade serous ovarian cancers, and ultimately peritoneal metastases. Dr. Krishnan graduated with a Ph.D. from Penn State University and received further training at the University of Chicago where he carried out preclinical validation studies and identified signals that could be used as biomarkers for risk and ultimately targets for prevention.