Data from Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis

<div>Abstract<p>The secreted lipid transporter apolipoprotein E (APOE) plays important roles in atherosclerosis and Alzheimer's disease and has been implicated as a suppressor of melanoma progression. The <i>APOE</i> germline genotype predicts human melanoma outcomes, with <i>APOE4</i> and <i>APOE2</i> allele carriers exhibiting prolonged and reduced survival, respectively, relative to <i>APOE3</i> homozygotes. While the APOE4 variant was recently shown to suppress melanoma progression by enhancing antitumor immunity, further work is needed to fully characterize the melanoma cell-intrinsic effects of APOE variants on cancer progression. Using a genetically engineered mouse model, we showed that human germline <i>APOE</i> genetic variants differentially modulate melanoma growth and metastasis in an APOE2>APOE3>APOE4 manner. The low-density lipoprotein receptor-related protein 1 (LRP1) receptor mediated the cell-intrinsic effects of APOE variants on melanoma progression. Protein synthesis was a tumor cell-intrinsic process differentially modulated by APOE variants, with APOE2 promoting translation via LRP1. These findings reveal a gain-of-function role for the APOE2 variant in melanoma progression, which may aid in predicting melanoma patient outcomes and understanding the protective effect of APOE2 in Alzheimer's disease.</p>Significance:<p><i>APOE</i> germline variants impact melanoma progression through disparate mechanisms, such as the protein synthesis–promoting function of the APOE2 variant, indicating that germline genetic variants are causal contributors to metastatic outcomes.</p></div>