Endocrine Abstracts

The long range objective of my laboratory is to understand the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland in health and disease. Recent efforts examine the hypothesis that Wnt/βcatenin signaling maintains the functional capacity of the adrenal cortex though the regulation of undifferentiated adrenocortical cell fate. Dysregulation of this system is predicted to result in abnormal adrenocortical growth and/or differentiation. Using cellular systems, mouse models together with genomic approaches with mouse and human adrenocortical carcinoma (ACC) samples, we aim to characterize the stem/progenitor cells of the adrenal cortex and uncover the mechanisms by which these cells are regulated by Wnt/βcatenin signaling in normal adrenal growth maintenance and cancer.

In the adrenal cortex, Wnt/βcatenin signaling is restricted to the subcapsular region. While these subcapsular undifferentiated adrenocortical cells are known to migrate centripetally into the cortical zones of the gland to populate the three zones of the adrenal cortex, the molecular mechanism underlying role of these cells in tissue homeostasis is poorly understood. We present data that support a role of Wnt/βcatenin signaling in the self-renewal and multipotent properties of these adrenocortical cells in vivo. We also characterize mechanisms by which loss and gain of Wnt/βcatenin signaling participate in the development of adrenal failure and ACC, respectively. ACC is an incredibly rare and routinely fatal disease with few effective treatments. Understanding the role of Wnt/βcatenin signaling in adrenocortical cell fate will lay essential groundwork for future therapies that target this pathway and downstream genes that are found in the course of these studies to participate in adrenocortical stem/progenitor cell biology.