Dr. Gary D. Hammer, M.D., Ph.D., is a medical endocrinologist specializing in the treatment of adrenal disease. Research projects in his laboratory are aimed at elucidating the mechanisms by which growth factor signaling and transcriptional programs initiate adrenal-specific growth and differentiation with an emphasis on dysregulated growth of adrenocortical stem/progenitor cells in development and cancer. Adrenocortical carcinoma (ACC) is a very rare endocrine cancer (1-2/million population/year) but its importance is magnified by its dismal prognosis, lack of therapies with proven efficacy and its association with several genetic syndromes.
Dr. Hammer's laboratory research looks at how adrenal tumors develop and become cancerous, and how certain genes and proteins contribute to the process. Capitalizing on the discovery by U-M researchers that the growth of many cancers is fueled by a very small number of cells within the tumor, referred to as cancer stem cells, Hammer's lab team has begun to unravel the complex control of the adrenal stem cell. They have identified cellular pathways that become mutated in these cells and lead to the development of adrenal tumors.
Summary of Current Lab Research Projects
Pod1 - (Michelle Wood)
Michelle's project has begun to investigate a protein, Pod1, which has been shown to be down-regulated in adrenal cancers and is proposed to maintain adrenocortical stem cells in their undifferentiated (non-hormone producing) state. Pod1 is thought to act to inhibit the differentiation of stem cells into the hormone producing cells of the adrenal through inhibition of a key regulator of steroid hormone production, SF1/Nr5a1. Understanding how stem cells are maintained in their undifferentiated state will provide insights into prevention of uncontrolled differentiation which can occur in cancers.
Investigation of the Key Factor in Adrenal Development (Mohamad Zubair)
Gene disruption studies revealed definitely that Ad4BP/SF-1 does not merely function as the steroidogenic gene regulator but as the factor required for establishing and/or maintaining the steroidogenic tissues. Ongoing studies are aimed at identifying the enhancer for definitive adult adrenal of Ad4BP/SF-1 and at determining what induces the enhancer function. The finding of enhancer is very important for identifying the basic information of transduction signal and transcription factor that include in cell fate transition events.
Wnt Signaling Pathways (Beth Starnes)
The Wnt signaling pathway has been implicated in the growth of many organ systems and specifically in the biology of adult stem cells residing in each organ. The transcription factor, β-catenin, is activated by Wnt signaling and stabilization of β-catenin has been reported in a number of endocrine tumors, including tumors in the adrenal cortex. Steriodogenic Factor 1 (SF1) is an orphan nuclear receptor involved in regulation of many steroidogenic genes. Both β-catenin and SF1 are essential for proper adrenal organogenesis and their dysregulation promotes adrenal tumorigenesis. Our laboratory studies the role of these signaling proteins in adrenocortical stem cell biology. One current project aims to determine the whole genome targets of -catenin and SF1 to discern genes required for adrenal homeostasis and identify drivers of adrenal tumorigenesis.
IGF2 (Joanne Heaton)
IGF2 is a developmentally important mitogenic factor that is one of the most upregulated genes in the vast majority of sporadic adrenocortical carcinomas (ACC). In addition, Beckwith-Wiedemann syndrome is a rare disorder in which patients display a strong predisposition to certain tumors including ACC. Patients with this condition also show increased IGF2 expression. In published studies we have used an IGF receptor inhibitor to target the IGF2 pathway both in ACC cell lines and mouse tumor xenografts and observed decreased cell proliferation and tumor growth. These studies were carried out with the hope they may provide new insights towards designing novel therapies in the treatment of adrenocortical carcinomas and, in fact, have led to ongoing clinical trials. Ongoing studies employ mouse models to examine the effects of a combination of IGF2 and β-catenin over expression, focusing on adrenal abnormalities.
Notch Signaling (Derek Simon)
Research on signaling pathways is essential for a comprehensive understanding of adrenal development and carcinogenesis. In addition to Wnt and Hedgehog, Notch signaling is another highly conserved developmental signaling pathway that has been shown to be involved in variety of organ systems. Our finding that the Notch ligand, Jagged1, is upregulated in a majority of ACCs has led us to hypothesize that Jagged/Notch signaling may contribute to ACC etiology by enhancing cell proliferation. The regulation of Notch signaling during embryogenesis also appears to be essential for normal adrenal development. Excessive Notch signaling causes adrenal failure while insufficient signaling leads to altered gland organization and maintenance. A better understanding of the role of Notch signaling in normal adrenal biology is expected to yield insights into the pathology of adrenal cancer.
Sonic Hedgehog pathway and the adrenal (Isabella Finco)
The Hedgehog pathway is a major signaling pathway involved in the organ development. Three different ligands that can initiate the molecular signaling, Sonic Hedgehog, Desert Hedgehog and Indian Hedgehog, are active in different regions of the vertebrate body and are involved in cell-fate decisions, cell proliferation and survival, and in body patterning. Dysregulated Hedgehog signaling pathway has been observed in many human cancers, such as basal cell carcinoma. Moreover, several studies have revealed a connection between the Sonic Hedgehog and the Wnt signaling pathway, which plays a critical role in the developing adrenal and in the formation of adrenal tumors. However, little is known about the Sonic Hedgehog pathway’s role in the adrenal biology and its contribution in the adrenal cancer. Using mouse models in which components of the Hedgehog pathway are altered, Dr. Hammer’s laboratory aims to evaluate the role of this potentially important pathway. Results of these studies are expected to provide a better understanding of the contribution of dysregulated hedgehog factors to adrenal carcinogenesis and may serve to create more successful therapies.