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MRF’s 25th Anniversary: Learning More about Persister Cells

For our 25th anniversary, we share a guest blog from Vito Rebecca, PhD from Johns Hopkins University Bloomberg School of Public Health:

As a scientist, a translational researcher and son to a mother who succumbed to cancer, my defining goal is to understand why existing therapies do not cure all cancer patients. My laboratory at the Johns Hopkins University Bloomberg School of Public Health investigates the underlying mechanisms that allow melanoma cells to metastasize and escape therapy, with an emphasis on identifying exploitable cancer cell vulnerabilities that have the potential for clinical translation.

There are an impressive number of FDA-approved therapy options available for melanoma patients consisting of either targeted therapy and/or immunotherapy that initially control and even eliminate the bulk of tumor cells. However, resistance arises frequently due (at least in part) to rare subpopulations of melanoma cells that persist through therapy, metastasize and ultimately regrow with acquired resistance. These “persister cells” are resistant to chemotherapy, targeted therapy and exhibit immune cell-evasive properties making them extremely difficult to kill.

We and others have characterized these aggressive persister cell subpopulations and identify common features including a dormancy-like state that allows long-term survival, high ability to metastasize to distant organs and stem cell-like properties, however it remains poorly understood how to best kill persister cells. In 2019, I received my first independent funding from the Melanoma Research Foundation (MRF) Career Development Award (funded by the Denver and Philadelphia Gala Fund-a-Grants) to experimentally dissect persister cell vulnerabilities that hold the promise to enhance our ability to eliminate the entire tumor and potentially increase the cure rate in patients with advanced disease. Through a novel genetic analysis of melanoma cells and stem cells, our promising preliminary data has identified the g-coupled receptor LPAR1 as a potential Achilles Heel critical for persister cell viability, their metastatic potential and their ability to escape therapy. The funding from the MRF is supporting our lab’s efforts to validate the utility of targeting LPAR1 (as well as downstream YAP1 and mTOR signaling nodes) through “multi-omic” analyses to curb melanoma metastasis and increase the efficacy of existing targeted therapy strategies. Currently, we are investigating the importance of LPAR1 in maintaining the clonal diversity and aggressiveness of persister cell subpopulations using single cell approaches. We believe the insights gained from these studies will become a useful resource for the melanoma research community.

The support of the MRF has also been instrumental in my career development by a) catalyzing my transition into an Assistant Professorship the following year as I launched my independent laboratory and b) sparking multi-institutional collaborations between my group at Johns Hopkins University and researchers with complementary areas of expertise at The Wistar Institute and the University of Pennsylvania. An accomplishment we are proud of that has stemmed from this work are the doctoral and post-doctoral trainees now involved with these studies, with a large number of them being underrepresented minorities in science.

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