Diversity Generating Oncogenes and Melanocyte Plasticity
The acquired genetic mutations that accompany each stage of melanoma progression are well established. However, acquisition of these mutations leads to a variety of different cell behaviors, only a fraction of which are themselves oncogenic. For example, introduction of the point mutation BRAFV600E into normal melanocytes can either drive malignant melanoma, terminate in a benign mole, or result in no observable behavioral change. BRAFV600E is therefore a mutation that drives phenotypic diversity, as opposed to a single obligate transformation. Phenotypic diversity could be derived from the triggering of several predefined pathways that occur with different probabilities or be the consequence of increased cellular plasticity. The Judson-Torres Lab uses a combination of single cell RNA sequencing, digital holographic cytometry, and CRISPR/Cas9-based precision engineering to determine which melanoma-associated mutations result in a single obligate phenotype, which mutations generate phenotypic diversity, and which mutations increase general melanocyte plasticity. We are particularly interested in the influence of the initial cell state (e.g., anatomical location, genetic background, age, differentiation status) and common environmental cues and compounds on the distribution of clinically relevant phenotypes.
Mechanisms of Melanoma Initiation and Progression
Metastasized melanomas are difficult to treat, can rapidly acquire resistance to many therapies, and are generally associated with low survival rates. However, prior to reaching this stage, melanomas first undergo several defined stages of progression, and, if detected early, melanomas are completely curable through excision. The Judson-Torres Lab seeks a better understanding of the molecular changes that either precede or accompany each stage of progression. Specifically, we explore the mechanisms that stabilize each stage against further progression, including microRNA regulation, cell-cell and cell-ECM interactions, stochastic transcriptional noise, epigenetic reprogramming, and allelic imbalance.
Early Detection and Prevention of Melanoma
A central objective of our group is to directly assess the potential of our basic discoveries to translate into clinical applications that aid patient care. The nature of our research lends itself in particular to either clinical studies that explore the utility of candidate biomarkers for early detection of melanoma or preclinical studies that assess the efficacy by which compounds increase or decrease the risk of melanoma initiation.