Apolipoprotein E2 Promotes Melanoma Growth, Metastasis, and Protein Synthesis via the LRP1 Receptor

Abstract 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. APOE germline genotype predicts human melanoma outcomes, as APOE4 and APOE2 allele carriers exhibit increased versus reduced melanoma survival, respectively, relative to APOE3 homozygotes. While the APOE4 variant was recently shown to suppress melanoma progression by enhancing anti-tumor immunity, the melanoma cell-intrinsic effects of APOE variants on cancer progression remain poorly characterized. By using a genetically engineered mouse model, we show that human germline APOE genetic variants differentially modulate melanoma growth and metastasis in a melanoma LRP1 receptor-dependent manner. We identify protein synthesis as a tumor cell-intrinsic process differentially modulated by APOE variants, with APOE2 surprisingly promoting translation via LRP1. Our findings reveal a gain-of-function role for the APOE2 variant in melanoma progression, raising important implications for other diseases impacted by APOE genetics. Significance Our work reveals that germline APOE variants differentially impact genetically initiated melanoma progression, with APOE2 acting as a promoter of tumor growth, metastasis, and a cell-intrinsic process—protein synthesis. These findings may aid in predicting patient outcomes and may partly explain the protective effect of APOE2 in Alzheimer’s disease.