The laboratory has shown that the orphan nuclear receptor SF-1 (steroidogenic factor-1) is absolutely required for proliferation of the adrenocortical stem/progenitor cells while the orphan receptor Dax-1 serves to maintain the multipotency of these cells in vivo. Moreover, the group has provided a novel paradigm by which a key stem cell renewal pathway (Wnt signaling) can influence nuclear receptor function, namely that beta-catenin can directly bind and activate SF-1 mediated transcription in the adrenal cortex. Targeted loss- and gain-of-function of canonical Wnt signaling results in loss and expansion of adrenocortical stem/progenitor cells and ultimate adrenal failure and adrenal cancer, respectively. 

Ongoing molecular studies detail the mechanisms by which such membrane-initiated signals mediate the cyclic entrainment of SF-1 transcription complexes - predicting a unique layer of regulatory control common to multiple classes of transcription factors. Work on inhibin null mice has unraveled a unique role of inhibin as a gatekeeper of adrenal versus gonadal differentiation in the adrenal gland. In the absence of adrrnal inhibin, unopposed TGFb2/Smad3 signaling in the adrenocortical stem/progenitor cell results in uncontrolled stem/progenitor cell expansion and ultimate differentiation into ovarian tissue. The positional cloning of the mutation responsible for adrenocortical dysplasia in mice by the Hammer group has provided clues to the role of telomere maintenance in these cells. As this gene was simultaneously described as a telomere regulatory protein, this is the first characterization of a viable tissue-specific defect in a mouse with a mutation in such a regulatory gene. 

Because Wnt signaling and telomere biology are intimately involved in stem/progenitor cell biology, the lab's current efforts are heavily weighted towards understanding the signaling and transcriptional mechanisms involved in the regulation of adrenocortical stem/progenitor cells in development and cancer. With U-M collaborators, Hammers lab is also investigating how gene profiles can be used to diagnose adrenal cancer or predict how well a patient will respond to treatment. They hope to develop new treatments, including targeted biological-based therapies designed to hone in directly on the cancer cells while sparing normal tissue. A national NCI-sponsored trial using a monoclonal antibody to the IGF1R receptor is the labs first of such therapies for adrenal cancer.