The role of MER/PROS1 in promoting stromal induced emergence from metastatic melanoma dormancy

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Project Summary The goals of this Pathway to Independence Career Development proposal are to request support for Dr. Fane to develop training in tumor dormancy and underlying cancer immunology and bioinformatics techniques to investigate how dormant melanoma cells located within metastatic tissues can regulate stromal cells to facilitate metastatic outgrowth and resistance to therapy. The training plan outlined in this proposal will take advantage of the extensive resources and career development programs available at Johns Hopkins. Dr. Fane has assembled a team of leaders in the field of melanoma, dormancy, immunology, and bioinformatics who will guide his training. Metastasis is the largest cause of melanoma deaths, with treatments failing to provide a durable response. While a subset of patients show-remarkable responses initially to therapy, most of them will have tumor cells lying dormant in distal organs that persist during therapy but are clinically undetectable. Eventually, these cells will ‘reactivate’ from dormancy to form metastatic colonies, now resistant to therapy. There are few labs that focus on melanoma dormancy and as such, there are no current treatments or diagnostic tools to identify and target dormant cells. The proposed studies are based on Dr. Fanes novel findings that upregulation of the tyrosine kinase receptor MER promotes cancer growth, which allows ‘reactivation’ of dormant melanoma cells within the lung. It isn’t known how ‘reactivated’ cells overcome targeting by the immune system, growth restrictive cues from lung fibroblasts, or how they become resistant to therapy. Dr. Fanes preliminary data first shows that MERhigh melanoma cells regulate lung fibroblasts to alter secretion of the extracellular matrix, changing it from being dormancy promoting to allowing melanoma outgrowth. Dr Fane has also shown that following ‘reactivation’ of melanoma within the lung, there is an increase in Myeloid Derived Suppressor Cells (MDSCs) and T-regulatory (Tregs) cells which inhibit the immune system from targeting cancer cells for destruction and are often a common feature in patients resistant to immunotherapy. Finally, Dr. Fane has shown that ‘reactivated’ melanoma cells secrete high levels of the soluble protein PROS1, which is known to be involved in regulating the activity of MDSCs, Tregs, and lung fibroblasts within other disease states, but has not been investigated in metastatic dormancy. Dr. Fane will explore the following scientific aims: 1) Determine whether MER induced secretion of PROS1 regulates lung fibroblast to promote outgrowth and therapy resistance and 2) Investigate the mechanism by which MER induced secretion of PROS1 by melanoma cells in the lung regulates immune cells and response to α-PD1. The completion of the scientific aims in this proposal will develop Dr. Fanes scientific and professional skills that are required to be an independent investigator into the field of dormancy and importantly, will provide novel insight into how cancer cells overcome targeted and immunotherapies in dormant, metastatic disease.