Graduation Year

2024

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Eric K. Lau, Ph.D.

Committee Member

Elsa R. Flores, Ph.D.

Committee Member

Keiran S. Smalley, Ph.D.

Committee Member

Ahmad Tarhini, M.D., Ph.D.

Committee Member

Jennifer A. Wargo, M.D., M.M.Sc.

Keywords

Adherens junction, Fucosyltransferase 4, L1 cell adhesion molecule, Melanoma metastasis, Sex hormone

Abstract

Melanoma incidence and mortality rates are historically higher for men than women, with an estimated ~47% more new cases and twice the lethality in men in the US in 2023. Consistent with these discrepancies, emerging studies have highlighted the tumorigenic role of the male sex hormone androgen and its receptor (AR) in promoting melanoma aggressiveness. However, underlying cellular and molecular mechanisms and their precise pathological contributions are not well-defined. We recently discovered a sex-associated disparity in melanoma fucosylation, the post-translational modification of proteins with the dietary sugar L-fucose. Fucosylation, the conjugation of fucose moieties onto different glycan linkages on target proteins by 13 different fucosyltransferases (FUTs), can influence the characteristics (e.g., stability, interaction, and activity) of target proteins which result in divergent cellular signaling. Here, we report a novel mechanistic relationship between androgen signaling and fucosylation-regulated network that facilitates the invasiveness and metastatic capacity of melanoma. In melanoma, androgen-activated AR transcriptionally upregulates FUT4, a key mediator for generating tumorigenic fucosylation that alters cellular adhesion dynamics and potently drives invasiveness in vitro and in vivo. Fucoproteomic profiling identifies L1 cell adhesion molecule (L1CAM) as a key downstream effector fucosylated by FUT4, which is required for AR-FUT4-induced melanoma metastasis. Single-cell level immunofluorescent assessment of a melanoma patient tumor microarray reveals a robust correlation of transcriptionally active AR, fucosylated L1CAM, and loss of cell-cell junction complexes with stage IIb-III tumors in male patients, consistent with the contribution of this mechanism to enhance the invasive capacity required for early stages of the metastatic cascade. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help to explain sex-associated disparities in clinical outcome and highlight AR-FUT4 axis and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma.

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