cAMP has distinct effects in multiple inflammatory cells and drugs that target cAMP signaling have shown promise as therapeutics for diseases such as psoriasis and atopic dermatitis. However, the exact mechanisms by which cAMP influences inflammatory cells in the skin remains poorly understood. We have taken a multipronged approach to dissect the role of cAMP in different inflammatory cells in the skin. We have established that specific sources of cAMP play distinct roles in the activation of T helper cells during psoriasis, atopic dermatitis, and allergic contact dermatitis. We are currently working on establishing the mechanisms by which these distinct cAMP signaling cascades regulate T helper cell development and activation. We are also leveraging our association with the Tri-Institutional Therapeutics Discovery Institute to develop a class of non-steroidal topical therapeutics for the treatment of inflammatory skin diseases.
cAMP has a long and complicated history as it relates to tumor growth and response to therapeutics. We have identified a novel nuclear specific cAMP microdomain that blocks the growth of multiple human and mouse cancer cell lines both in vitro and in vivo. This nuclear signaling domain is activated early in tumorigenesis and when lost leads to tumor growth and invasion. We have established that nuclear cAMP regulates a novel signaling cascade that inhibits the Hippo pathway and leads to EMT transition. Antibodies that detect this pathway in the nucleus have diagnostic and prognostic utility, and we are working to understand the mechanisms by which this pathway inhibits tumor growth, invasion, and response to therapy.
Melanoma changes as it invades through the skin and metastasizes to more distant sites. It has become clear that melanoma adapts to these changing environments, though genetic mutation is not the mechanism for adaptation. Changes in tumor metabolism are associated with invasion and metastasis but the mechanisms are poorly understood. Melanoma invasion and metastasis are associated with increases in melanin production. Melanin is the pigment made by melanocytes and can impact reactive oxygen species and other metabolic pathways. Increased melanin is associated with tumor progression and therapeutic response. However, the manner in which melanin production changes in melanoma is unclear. We recently discovered a new mechanism that controls the pH of the melanosome, the organelle that controls melanin synthesis. We have also learned that melanosome pH changes in response to cellular pH and metabolism and provides a link between the microenvironment and melanoma progression. To investigate the interplay between the microenvironment, melanosome pH, and melanoma, we have developed numerous cell and mouse models and human melanoma organoid cultures. We have also developed a novel LC/MS method that allows us to trace tyrosine metabolism along with glucose and other metabolic pathways. By utilizing these tools, we seek to establish the mechanisms by which melanoma responds to changes in the microenvironment during invasion and metastasis.