2020 Collaborative Research Development Grant Recipient — Sandra Orsulic, PhD

Project Summary

Cancer surgery and chemotherapy can be life-saving, however for some cancers, they may also cause the development of future metastases. Tumor manipulation during surgery can result in the release and dissemination of malignant cancer cells which may find a metastatic niche at distant sites. Additionally, unavoidable damage to surrounding normal tissues by surgery and chemotherapy may generate local or distant microenvironments permissive for tumor growth, known as treatment-induced pre-metastatic niches. Several processes related to surgery- and chemotherapy-induced trauma are thought to facilitate postoperative metastatic spread, including inflammatory and wound healing responses that can exacerbate extracellular matrix remodeling, angiogenesis, tumor cell migration, attachment, and proliferation. This can ultimately result in carcinomatosis, a widespread intraperitoneal growth of numerous cancer cell deposits on mesothelial surfaces, which is typically associated with poor survival.

Mesothelial cells that line the peritoneal cavity are thought to be the “first line of defense” against carcinomatosis. Surgery and chemotherapy cause severe injury to the mesothelial layer, expose sub-mesothelial fibroblasts to cancer cells, and induce a wound healing process conducive to cancer cell implantation. Potential strategies to circumvent some of the unwanted effects of surgery include the use of anti-inflammatory agents to suppress the inflammatory response to mesothelial injury and perioperative chemotherapy to eradicate residual cancer cells before they attach to the injured sites. However, to develop therapeutic strategies that are truly effective in preventing or arresting the pro-metastatic processes, it is important to fully understand the mechanisms of mesothelial wound healing and identify the time interval when the injured mesothelium is most vulnerable to cancer cell seeding.

We developed an immunocompetent mouse model that recapitulates the pathophysiology of mesothelial injury-facilitated peritoneal carcinomatosis. We demonstrated that the early stages of mesothelial wound healing are characterized by an influx of specific immune cells, such as neutrophils and macrophages, and factors that promote fibrosis. We will use this model to test the hypothesis that the recruitment of specific immune cells and/or fibroblasts in different stages of peritoneal wound healing facilitates carcinomatosis and offers new targets for prevention. Our goal is to identify specific immune cell types and molecular signals that can be temporarily depleted or functionally inactivated to prevent mesothelial injury-associated cancer cell engraftment. Additionally, we will profile chemonaive and chemoresistant tumors from ovarian cancer patients to identify the cellular and molecular hallmarks of the chemoreistant state that can be targeted to potentiate the effects of chemotherapy and prevent recurrence. The preclinical data from this study will be the basis for future clinical trials to prevent the metastasis-promoting effects of surgery and chemotherapy and make these interventions even safer and more beneficial to patients.

Bio

Sandra Orsulic, PhD, is a Professor of Obstetrics and Gynecology at Cedars-Sinai Medical Center and a Professor-in-Residence of Obstetrics and Gynecology at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Prior to joining Cedars-Sinai, Dr. Orsulic was Assistant Molecular Pathologist at the Massachusetts General Hospital in Boston, where she also served as Assistant Professor of Pathology at Harvard Medical School. Her research includes studying the mechanisms by which the microenvironment contributes to cancer initiation and metastatic progression, identifying molecular markers for early cancer detection, and generating suitable pre-clinical models for testing targeted therapies. Dr. Orsulic’s research on ovarian cancer has been funded primarily by the National Institutes of Health (NIH), Department of Defense (DoD), American Cancer Society (ACS), and Ovarian Cancer Research Alliance (OCRA). Her studies have been published in peer-reviewed journals such as Nature, Cancer Cell, Proceedings of the National Academy of Sciences, USA and Cancer Research. Dr. Orsulic is a member of the OCRA Scientific Advisory Committee and serves on several editorial boards and NIH review panels.