The laboratory is interested in understanding the evolutionary dynamics of tumor metastasis. This includes identification of genomic changes within the cancer cell itself, and studies to determine how these changes interact with the host genetic background. Potential projects for those joining the laboratory include:
How the cancer genome changes over the life of metastasis
The cell(s) in which tumors arise have a dominant effect on the biology of the subsequent tumor. We are interested in understanding how lineage-specific factors in the cell of origin regulate the metastatic phenotype, and the subsequent genomic landscape of the tumor cell itself. Why do some cell lineages sustain BRAF mutations while others sustain NRAS mutations or MITF amplifications? Because this is a continuously dynamic process, the evolution of these genomic changes is analyzed forward in time, utilizing clonal and single-cell sequencing technologies along with phylogenetic reconstructions.
How host factors modulate the landscape of metastasis
Within the microenvironment of the tumor, innumerable cell types and subtypes — including immune cells, endothelial cells, fibroblasts, and keratinocytes — modulate both the phenotype, and likely the genotype, of the tumor cells. In each step of metastasis, there are genetic programs required in each novel microenvironment. The use of unbiased, forward genetic screens in zebrafish provides a unique platform to identify novel genes that allow the host to promote or impair metastatic progression.
Lineage-specific factors in melanoma
Gene expression profiling of both zebrafish and human melanoma demonstrates that these tumors express a significant number of genes associated with the embryonic neural crest, the tissue that differentiates into the adult melanocytes. These lineage-specific genes, including crestin, sox10, mitf, and ednrb, are required for the development of the melanocyte lineage during embryogenesis. We asked whether these lineage specifiers are required for melanoma initiation and progression. Using a chemical genetic approach, we found that small molecule inhibitors of the DHODH metabolic enzyme (typified by leflunomide) were able to suppress embryonic expression of the neural crest lineage genes by interfering with the process of transcriptional elongation. Our work has established that transcriptional elongation serves as a gene regulatory mechanism in the embryonic neural crest as well as in melanoma tumors.
Development of new models of metastatic pancreatic cancer in zebrafish
While our previous work has primarily focused on melanoma biology, we are now developing several new models of pancreatic adenocarcinoma in the zebrafish. We are using promoters that drive pancreatic-specific expression of CreERT2, combined with floxed alleles of KRASG12D, to develop inducible pancreatic cancer models. We will categorize tumors with low versus high metastatic propensity at the cellular and genomic level. We anticipate using these models as the basis of screens to identify genetic and chemical modifiers of the metastatic phenotype in pancreatic cancers.