Student Theses and Dissertations

Author

Nneoma Adaku

Date of Award

2023

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Tavazoie Laboratory

Abstract

Genetic polymorphism of the secreted lipid transporter apolipoprotein E (APOE) plays important roles in the development of atherosclerosis and Alzheimer’s disease. More recently, three common APOE alleles have been implicated as modulators of melanoma progression and survival. Melanoma patients born with a copy of the APOE4 allele exhibit improved disease survival and responses to immunotherapy. Conversely, APOE2 allele carriers experience substantially worsened survival outcomes compared to APOE4 carriers and APOE3 homozygotes. These survival differences are partly governed by effects on the immune system, as the APOE4 genotype augments anti-tumor immunity. However, APOE variants also exert direct suppressive effects on melanoma cell metastatic behavior in an APOE4>APOE3>APOE2 order of potency. The molecular processes underlying the melanoma cell-intrinsic response to APOE variants are poorly characterized. In this thesis I describe the generation and characterization of a genetically engineered mouse model for melanoma that expresses each of the human APOE alleles. I show that this autochthonous model closely recapitulates the APOE2>APOE3>APOE4 order of melanoma progression observed in human patients. Transcriptomic analysis of tumors derived from this genetic model revealed upregulation of mRNA translation in APOE2 melanomas relative to APOE4 melanomas. After experimental examination of the effects of APOE variants on melanoma translational efficiency, I report the discovery that APOE2 acts in a gain-of function manner to enhance pro-tumorigenic protein synthesis in melanoma cells. Melanoma cell-specific deletion of the APOE receptor LRP1 in the genetic mouse model abolished differences in tumor growth, metastasis, and protein synthesis between the APOE2 and APOE4 genotypes, thus revealing a melanoma cell-intrinsic APOE2/LRP1 axis that serves to promote melanoma progression. Analysis of a melanoma patient RNA-Seq dataset demonstrated upregulation of mRNA translation processes in APOE2 patient tumors, thus providing clinical relevance for these findings. Altogether, this thesis identifies a potentially therapeutically targetable pathway in melanoma and reveals a novel gain-of-function role of the APOE2 allele, which may have implications for other diseases impacted by APOE genetics.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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