Project Summary - Overall The clinical landscape of melanoma is evolving rapidly, however, a significant fraction of individuals fail to respond to frontline therapy, and another significant fraction of melanoma patients develop resistance. In order to improve the response to frontline therapies, we have previously focused on inhibiting survival pathways, including autophagy, senescence and proteostasis. In the new funding cycle, we extend this focus toward targeting the melanoma microenvironment. Targeted therapies designed to inhibit tumor-intrinsic signaling do not contemplate the influences of the microenvironment, and the recent success of immunotherapy is a reminder of how important the consideration of the microenvironment is. Our data are revealing that the normal aging of stromal cells creates a microenvironment that promotes the activation of signaling pathways that circumvent those targeted by therapies such as vemurafenib, making the one gene, one drug approach less likely to be successful. Additionally, the crosstalk between stromal and immune cells in the tumor microenvironment is vastly underexplored. We believe that genetic drivers in the tumor cell, or specific checkpoints on immune cells cannot be effectively targeted, without the consideration of the crosstalk between those cell populations and other cells in the microenvironment. The Program consists of four well-integrated projects, from a team that has worked extremely well together over the last five years, publishing numerous high-impact collaborative papers. The evolution of this P01 into its new form is truly a reflection of these concerted efforts, evolving from targeting cell fate, to a realization that cell fate can be differentially affected by its microenvironment. The four Projects are designed in order to achieve a fully coordinated understanding of how multiple factors (but with a focus on aging) in the tumor microenvironment contribute to therapy resistance. The alteration of lipid profiles in stromal, immune and tumor cells is emerging as a key driver of resistance. The Projects will work together to understand the impact of lipid production, accumulation, uptake, metabolism and catabolism in tumor cells. Using the novel compounds developed within the current funding cycle of the grant, we will target tumor/TME crosstalk, and explore novel ways in which to disrupt it.