Our research focuses on the molecular pathogenesis of melanocytic neoplasia. We use –omics approaches to survey patient samples of melanocytic neoplasms of different progression stages to identify genetic alterations that are associated with specific progression stages or represent therapeutic targets. We use functional studies to evaluate the contributions of individual genetic alterations to the neoplastic phenotype. We are studying the mechanisms of how moles form and what makes them cancerous. Our goal is to develop objective diagnostic algorithms that can assess how far an individual patient’s tumor has evolved and how treatment is best be tailored to the individual patient.
Melanoma classification and evolution
We identified specific melanoma subtypes that can be distinguished based on molecular, clinical, histologic and epidemiological features. The correlation between specific mutations and clinical features -- such as anatomic site, degree of cumulative UV exposure, and age of onset -- confirmed prior notions about the existence of distinct melanoma subtypes. The insights from genetics allowed us to refine prior clinically-based classifications and develop a molecular taxonomy, which forms the the blueprint for the new WHO Classification of Skin Tumors. We found that the multiple genetic alterations detected in advanced melanomas of a given subtype accumulate in a stereotypical order, starting with mutations activating oncogenes followed by immortalizing mutations and disruption of several tumor suppressor pathways. However, our understanding of the genetic landscapes of early lesions, their interaction with the immune system, and ultimate evolution to melanoma remains incomplete.
Paradigm of Taxonomy Development
A group of primary neoplasms that his heterogeneous with regard to evolutionary stage and melanoma subtype affiliation is separated by subtype (shape/color of the symbol) and evolutionary stage (size of the symbol)
http://www.annualreviews.org/eprint/qcyB23jQvUnRyuhYHNbU/full/10.1146/annurev-pathol-012513-104658
The goal of our efforts is to develop precision melanoma diagnostics that can identify to which subtype a given lesion belongs and how far it has evolved to better guide clinical management of early stage patients. respective pre-neoplastic lesions and develop sets of biomarkers that assess critical changes in neoplastic and stromal cells to accurately distinguish harmless neoplasms from those that are destined to progress. and recurrent mutations of KIT in acral and mucosal melanoma, which since has become a validated therapeutic target. We identified a range of different fusion kinases in 'wild-type' melanomas and melanocytic neoplasms in children that represent novel therapeutic targets.
Uveal melanoma
We discovered that oncogenic activation of the Gαq signaling pathway is a defining feature of uveal melanoma. A major focus of the lab is to understand how this pathway drives tumor progression and how it can be therapeutically inhibited. We are also investigating how uveal melanomas evolve as they become metastatic and what factors govern their unique ability to metastasize to the liver. We found that melanocytic neoplasia links the signaling downstream of Gαq to the MAP-kinase pathway. We are now exploring how this cascade can be blocked.
PKC delta and epsilon mediate ERK activation in uveal melanoma with Gaq pathway mutations through the RAS exchange factor RasGRP3. These signaling compents are novel therapeutic targets for uveal melanoma
Acral melanoma
We found that melanoma that originate from the non-hair-bearing skin of palms and soles and nail apparatus have distinctive features from cutaneous melanomas. The express a high degree of genomic instability that is characterized by frequent gene amplifications and structural rearrangements. The alterations suggest an underlying DNA repair defect, which could be therapeutically exploited. We are currently sequencing a large cohort of acral melanoma of different progression stages to identify the sequential order with which genetic alterations accumulate as acral melanoma evolve. Using a collection of cell lines we are evaluate the characteristic genetic alterations at high resolution to obtain clues about the underlying repair defects.
Field cells in acral melanoma
Melanocytes that look histologically normal but have similar genetic alterations as cells in a nearby melanoma in situ indicate a field effect that explains, why some melanomas recur after an apparently complete excision.
Spitz tumors
Spitz tumors are distinct melanocytic neoplasia that range from benign Spitz nevi to Spitz melanomas. We identified that they have characteristic genetic alterations such as mutations in HRAS and fusion of kinase genes as distinct oncogenic drivers. We are working on improved methods to help with their diagnostic classification to improve on current methods, which are unable to reach unequivocal diagnostic assessment in a substantial portion of cases.
Gain of chromosome 11p in a Spitz tumor with HRAS mutation