Presentation description

Adrenocortical carcinoma (ACC) is an aggressive cancer of the adrenal gland with a five-year survival rate of less than 50%. Peak incidence after age 50 suggests links to aging, yet the underlying mechanisms remain poorly defined. A hallmark of aging is the accumulation of senescent cells, contributing to age-related pathologies, including cancer. Prior studies suggest increased Wnt signaling may act as a senescence-associated driver of tumorigenesis. We investigate this by utilizing a Znrf3 conditional knockout (ZKO) mouse model that recapitulates age-associated tumor initiation. We hypothesize that senescent cells facilitate ACC development via age-induced upregulation of Wnt signaling.
To test this, we conducted qPCR analysis of six Wnt target genes in young (9-week) and aged (44-week) ZKO mice. This affirmed increased Wnt activity with age. We are conducting immunohistochemistry (IHC) to quantify LEF1, a transcription factor marking high Wnt signaling, in aged adrenal tissues from a senescence-reporter mouse model (p16-FDR) where senescent cells are either retained or removed. Co-immunofluorescence (Co-IF) staining of LEF1 and p16 is also underway to evaluate spatial colocalization. We anticipate LEF1 and p16 will colocalize in adrenal tissues with intact senescent cells, and that this association will be diminished following senescent cell ablation.
These findings may uncover age-associated molecular mechanisms promoting ACC and support developments toward targeted therapies, such as drugs that eliminate senescent cells (senolytics) or Wnt-modulating drugs. By elucidating the interplay between senescence and Wnt signaling in ACC, we aim to inform precision treatment strategies and improve outcomes for a disease with limited therapeutic options.