Richard White, MD, Ph.D, is a physician-scientist at Memorial Sloan Kettering Cancer Center. His laboratory is interested in the ways in which developmental programs affect cancer progression, and how these programs are altered by the microenvironment. These questions have particular relevance for metastasis, a major cause of cancer morbidity. To address these questions, we primarily utilize the zebrafish as a model for melanoma, given its strengths in genetic manipulation and imaging, which is enhanced in our previously developed transparent casper strain of fish. Using a transgenic model of BRAFV600E induced melanoma, we discovered that tumor initiation requires establishment of a permissive neural crest program which includes genes such as SOX10 and crestin. Using a combination of in vivo imaging, genetics and chemical screens, we have identified transcriptional elongation as a key regulatory step in the expression of these neural crest genes. More recently, we asked why some developmental stages were more susceptible to BRAF. This revealed that a large number of chromatin modifying genes (e.g. ATAD2) are intrinsically expressed at a higher level in the neural crest compared to melanocytes, and these genes regulate the ability to respond to BRAF. This establishes a paradigm in which developmental chromatin programs are a determinant of how those cells respond to mutations, which we refer to as oncogenic competence. Finally, we have established systems to explore how the tumor microenvironment, and cell-cell interactions more broadly, influence these gene programs to promote phenotypes such as metastasis. This work has centered largely on adipocytes, a major component of the skin microenvironment. We found that adipocytes act as lipid donors to the nascent tumor and dramatically alter the transcriptional program of the melanoma cell towards a more invasive state. These lipids act as both signaling molecules but are also a major metabolic source of epigenetic reprogramming the melanoma cell. These observations lead to the idea that microenvironmental adipocytes can drive metastasis via changes in both metabolism and epigenetic state of the cancer cell. He has been awarded the NIH Director’s New Innovator Award, as well as awards from the Melanoma Research Alliance, the Pershing Square Foundation Award, and the Mark Foundation ASPIRE award.
