Hammer Laboratory
Research

Research

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

Molecular roles of ZAC1 in adrenal cortex development and cancer (Holly Hung)

Zac1, also known as Plag1 or Lot1 was initially identified in in a tissue culture model of ovarian cancer [3]. This gene encodes a C2H2 zinc finger protein thought to function as a tumor suppressor. With key developmental roles in many tissues including pituitary gland [4], retina [5], and skin [6], Zac1 has been shown to regulate cell cycle control and apoptosis in a cell-type specific manner. While it is know to be faintly expressed in adult adrenal glands, the normal function and biology of Zac1 is unknown.

 

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 p roliferation 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.

 

Post-Translational Regulation of Sf1 in Adrenal Development (Yewei Xing)

Sf1 (NR5A1) is an essential nuclear receptor in adrenal development and homeostasis. While it is well established that Sf1 dosage be critical for the proliferation of adrenocortical cells, recently, Sf1 post-translational modification has also been shown to regulate its function and activity. Previous study suggested that SUMOylation of Sf1 could influence its binding activity with CDK7, phosphorylation status, and thus change downstream gene transcription. Current projects focus on using different mouse models to study the roles of phosphorylation and SUMOylation on Sf1 and how they influence adrenal development and homeostasis in vivo.

 

The Orphan Nuclear Receptor SF-1 (Christopher LaPensee)

The orphan nuclear receptor SF-1 is an important mediator of normal growth and homeostasis in the adrenal gland. This transcription factor regulates steroidogenesis in differentiated adrenal tissue but also is essential for adrenal development. Adrenal glands and gonads do not develop in SF-1 deficient mice, highlighting the importance of SF-1 expression during development. My research focuses on the mechanisms by which Sf-1 expression is regulated in a temporospacial manner during adrenal gland development.

 

ZNRF3 (Kaitlin Basham)

I joined the Hammer Lab as a postdoctoral research fellow in September 2014. Previously, I completed my graduate training at the University of Utah, where I studied pathways that regulate normal mammary gland development and how they may be disrupted during breast cancer progression.

In the Hammer laboratory, I am studying a gene called ZNRF3, which was recently identified by The Cancer Genome Atlas Project as the most commonly altered gene in adrenocortical carcinoma (ACC). Specifically, ZNRF3 is deleted or mutated in nearly 20% of human ACCs. In light of these recent findings, we are studying the role of ZNRF3 during both normal adrenal development and ACC progression. We hope to uncover biology about ZNRF3 that ultimately aids in the development of innovative therapeutic strategies for the treatment of ACC.

 

CCDC80 and the adrenal extracellular matrix (Donald Little)

CCDC80 is a secreted protein recently discovered to be upregulated upon Beta-catenin stabilization. The current project involves defining the molecular interactions of CCDC80 and its effect on cell motility, adhesion, and the extracellular matrix in development and cancer.

 

Adrenocortical carcinoma (ACC) (Morgan Penny)

Adrenocortical carcinoma (ACC) is a rare and aggressive cancer that affects 1-2 people per million in the United States annually. Oncogenic β-catenin mutations occur in ~20% of all ACCs and are associated with poor prognosis. I am working to define the signature of proteins that are expressed in ACCs characterized by oncogenic β-catenin mutations, and their role in cancer proliferation, invasion, and metastasis.