Endocrine Abstracts

Adrenocortical carcinoma (ACC) is a routinely fatal cancer with no effective treatments. Understanding the genetic landscape of ACC is essential to develop novel therapeutic strategies. Recent large-scale cancer genomics projects have revealed core signalling pathways frequently altered in human ACC tumours, including the Wnt/b-catenin pathway. Aberrant Wnt activation is a hallmark of ACC observed in ~40% of tumours, and can be driven by diverse mutational events. These include well-characterised activating mutations in CTNNB1 (b-catenin) as well as newly identified loss-of-function alterations in ZNRF3, an E3 ubiquitin ligase that promotes Wnt receptor degradation. To study the functional role of ZNRF3 loss in ACC tumourigenesis, we developed a new mouse model to specifically ablate Znrf3 in the adrenal cortex. Our studies reveal that Znrf3 loss is permissive for ACC tumour progression, but not completely sufficient. We identify ageing and sex as key extrinsic factors that cooperate with Znrf3 loss by reshaping the immune microenvironment in order to permit malignant transformation. Further, we demonstrate that sex steroid hormones are a potent regulator of the anti-tumour immune response in the adrenal. Collectively, our studies highlight the intersection between paracrine Wnt signalling and endocrine hormone signalling in the pathogenesis of ACC. These pathways have important clinical implications and may be exploited for therapeutic benefit.