The adrenal cortex as a model of cellular renewal and progenitor cell dynamics
The adrenal cortex is a vital endocrine organ that produces steroid hormones in response to different physiological demands. These hormones are essential for life and regulate key biological processes, such as control of blood pressure, metabolism, reproduction, stress, and the immune response. In order to achieve both a rapid and precise response, the adrenal cortex employs hormonal feedback loops that act on functionally distinct adrenocortical zones. These layers, the outer zona glomerulosa, intermediate zona
fasciculata, and inner zona reticularis, produce mineralocorticoids, glucocorticoids, and androgens, respectively. Functional zonation within the adrenal cortex is established by centripetal differentiation, where stem and progenitor cells located in the outer portion of the gland give rise to concentric layers of differentiated cortex. The adrenal capsule, a mesenchymal layer surrounding the cortex, acts as a critical stem cell niche to support this process of continual cell renewal.
Our lab is interested in understanding the molecular signaling pathways that regulate cellular renewal of the adrenal cortex. These signaling mechanisms have important clinical implications for regenerative medicine to treat conditions of adrenal hypofunction, including congential adrenal hypoplasia, congenital adrenal hyperplasia, Addison’s disease, and adrenal atrophy from chronic exogenous glucocorticoid therapy. Moreover, these mechanisms are often dysregulated in cancer and may be important therapeutic targets to suppress tumor growth.
ZNRF3 as a novel regulator of the Wnt signaling pathway in adrenal cancer
Adrenocortical carcinoma (ACC) is an aggressive form of cancer that arises in the adrenal cortex. ACC is often diagnosed late and progresses rapidly, resulting in significant morbidity and poor outcomes. Since ACC is often diagnosed at an advanced stage, surgical resection is limited to a small cohort of patients and treatment is otherwise restricted to cytotoxic chemotherapy, radiation, and the adrenolytic drug mitotane. Consequently, more effective therapies are critically needed for the treatment of ACC.
To identify new potential therapeutic targets in ACC, large-scale cancer genomics projects (including The Cancer Genome Atlas project) molecularly characterized tumor tissue from human ACC patients. Among the newly identified genetic alterations, these studies identified loss of ZNRF3 as one of the most frequent genomic alterations in human ACC patients. Further, loss of ZNRF3 is associated with significantly decreased overall survival.
Results based on data from the TCGA Research Network
ZNRF3 and its homolog, RNF43, are E3 ubiquitin ligases that negatively regulate Wnt/beta-catenin signaling by controlling availability of Wnt receptors. ZNRF3 and RNF43 are thought to function as critical tumor suppressors since they are inactivated in a wide range of human cancers, including liver, ovarian, and pancreatic. To understand the molecular consequences of ZNRF3 loss in adrenal cancer, we generated an adrenal-specific Znrf3 conditional knockout mouse. We observed profound adrenocortical hyperplasia at 6 weeks of age due to a precise increase in intermediate-level Wnt/beta-catenin signaling (more details). Moving forward, we are interested in understanding beta-catenin-independent signaling pathways that are regulated by ZNRF3 during both adrenal homeostasis and cancer.
Paradoxical roles of cellular senescence in cancer
Cellular senescence is a normal biological stress response that blocks cell cycle progression to limit the propagation of damaged, potentially pre-malignant cells. Once arrested, senescent cells recruit phagocytic immune cells to facilitate extensive tissue remodeling. This highly dynamic process has traditionally been viewed as a permanent form of growth arrest, thus protecting against tumorigenesis, and many anti-cancer therapies act by inducing senescence. However, more recent studies suggest that cellular senescence may actually promote cellular plasticity and aggressive tumor phenotypes long-term. These observations challenge the conventional view of senescence as irreversible and suggest that senescent cells, including those induced by therapy, have the capacity to contribute to tumor relapse.
Our lab is interested in understanding the molecular mechanisms that mediate these seemingly paradoxical roles of senescence in cancer using a newly developed in vivo model of adrenal tumorigenesis. These studies will help inform the use of senolytics (drugs designed to eliminate senescent cells), which are emerging as a promising area of cancer drug development.
Schematic created using BioRender.com
Orthotopic ACC xenograft models using ultrasound-guidance
Our long term goal is to develop new therapeutic strategies for the treatment of ACC. We are particularly interested in senolytic compounds that are already in development for other cancer types. To facilitate the preclinical development of these therapies for ACC, we are establishing orthotopic xenograft models using both mouse and human-derived tumor cells. We have implemented ultrasound imaging, which is an efficient and non-invasive approach for injection and tumor monitoring in real-time. These models will enable us to study the functional impact of senescent cells on tumor growth and progression, and to test the efficacy of senolytic agents at effectively eliminating senescent adrenocortical cells.