Our research group is interested in elucidating basic mechanisms of stem cell self-renewal and differentiation, and regulation of intracellular signaling pathways. We are also trying to understand how the stem cell microenvironment, or niche, is controlled at the molecular level, and how stem cells and their nursing cells cooperate to maintain homeostasis. To investigate these processes and their dysregulations, we use two model systems: signaling within the germ cell niche in the testis, and signaling in thyroid cancer cells.
Molecular Regulation of the Germ Cell Niche:
We previously identified the transcription factor ETV5 as a regulator of male germ cell maintenance and homing in the testis. ETV5 is expressed by the nursing Sertoli cells and regulates expression of several chemokines such as CCL9. We also recently discovered that NOTCH signaling in Sertoli cells regulates other fundamental aspects of the germline stem cell niche. For example, NOTCH activity in Sertoli cells has a repressing function that balances the effects of the growth factor GDNF and the enzyme CYP26B, two molecules that are crucial to maintain the undifferentiated state of germ cells. By using mouse models of overexpression or knockout of NOTCH signaling, we are investigating how dysregulations of the niche lead to male infertility or contribute to the pre-cancerous state of carcinoma-in-situ (CIS).
Understanding the Role of Environmental Toxicants on Stem Cells:
We are also interested in understanding the effects of environmental toxicants and emerging technologies (e.g. nanomaterials) on the self-renewal and differentiation of germline stem cells, which possibly could impair male fertility. We recently demonstrated that silver nanoparticles and plasticizers such as phthalates disrupt the function of crucial kinases mediating signaling triggered by GDNF: Fyn kinase and ERK1/2. Silver nanoparticles also impair the function of Leydig cells, which normally produce testosterone. Another goal in our lab is to understand/prevent the impact of certain targeted cancer therapies on fertility in male patients.
Understanding Resistance to Tyrosine Kinase Inhibitors in Papillary Thyroid Cancer Cells:
Mutations in B-RAF kinase, a mediator of RAS signaling, are widely observed in papillary thyroid cancer (PTC) cells. These mutations activate downstream kinases along the MAPK pathway, resulting in the dependence of thyroid cancer cells upon this cascade to proliferate. While many patients respond to treatment with the B-RAF inhibitor vemurafenib, resistance can occur over time. The mechanism of acquired resistance is not completely understood, nor is it clear which drug should be started after progression. Because this mechanism is likely cell-type dependent, we are using different human cell lines (thyroid and non-thyroid cancer cells), human thyroid cancer samples and mouse genetic models to understand post-translational alterations that might potentiate/induce this acquired resistance. Specifically, we use microarray analysis, tissue arrays and reverse phase protein arrays (RPPA) to investigate novel molecules and signaling pathways that help bypass B-RAF signaling inhibition.