Our research program uses innovative genetic and genomic approaches, using both Sleeping Beauty transposon mutagenesis data from mouse cancer models and somatic mutation data from human cancer genomes, to discover the genetic and epigenetic events that initiate, progress, and contribute to acquired therapeutic resistance during the evolution of melanoma and non-melanoma skin cancers.
Cancer driver discovery continues to advance research with the promise of identifying genetic and epigenetic determinants that may contribute to new diagnostic markers and targeted therapeutics. The overarching goal of our research program is to define the functions of cancer drivers in the pathogenesis of skin cancer.
Our Cutaneous Cancer Driver Discovery Program (C2D2P) is currently focused on defining cooperating mutational events that drive normal melanocyte transformation to cutaneous Melanoma (cuMEL) and normal keratinocyte transformation to cutaneous Squamous Cell Carcinoma (cuSCC). We use a high-throughput mouse modeling platform and human cell culture models to functionally validate co-mutated drivers that propel initiation and progression of cuMEL and cuSCC.
Our current efforts are centered on the creation of a new generation of pre-clinical mouse models to probe in vivo drug resistance mechanisms and therapeutic target gene/pathway selection with demonstrated biological importance and translational application. Applying this information in the context of human cancer will advance cutaneous oncology research.
Cutaneous Melanoma Projects
- In collaboration with Karen M. Mann, we reported SB Pan Cancer Driver Discovery in our SBCDDB project published in Nucleic Acids Research. Learn more at http://sbcddb.moffitt.org/.
- We reported the genetic drivers of BrafV600E melanoma in Nature Genetics. Read more: PMID: 25848750.
- In collaboration with Cristin G. Print, we reported the MelanomaDB, a web tool for integrative analysis of melanoma genomic information at Frontiers in Oncology.
Cutaneous Squamous Cell Carcinoma Projects
- We reported the identification of cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression published in PLoS Genetics.
- In collaboration with Karen M. Mann, we demonstrated that there are oncogene independent routes to drive cancer development, reported in paper "promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation" published in Cancers.
- In collaboration with Kenneth Y. Tsai, we reported non-invasive assessment of epidermal genomic markers of UV exposure in skin in Journal of Investigative Dermatology.
Building SB-GEMMs to Dissect the Roles of Tumor Heterogeneity in Cancer Initiation, Progression and Prevention
Despite being critical for oncology modeling, traditional genetically engineered mouse models (GEMMs) often exclude mechanisms to generate and sustain somatic inter- and/or intra-tumor heterogeneity (ITH) that limits their translational value to discover and test effective prevention treatment strategies in preclinical systems that model the ITH complexity of human melanoma. To address this, we have built a new class of immune-competent preclinical SB-GEMMs, by harnessing Sleeping Beauty (SB) transposon insertional mutagenesis to generate the ITH within traditional GEMM genetics background, that can be used to effectively test and design precision prevention and treatment strategies in vivo.
Melanoma monotherapy treatment outcomes are heterogeneous. Cartoon of typical treatment responses to single molecularly targeted drugs; most cutaneous melanoma patients ultimately fail or relapse (top panel). The somatic inter- and/or intra-tumor heterogeneity in SB-GEMMs more closely matches that observed in human cutaneous melanoma patients with extensive branching of genetic tumor heterogeneity compared with traditional GEMMs. Our lab petroglyph (shorthand using symbols) for this project domain: ⇜SB⟿🐀 ℞ Ω