Our studies seek to define genetic changes that drive progression of melanoma, the most aggressive and deadliest skin cancer. New technologies have yielded a wealth of data describing the genomes of cancers. These studies are retrospective. They offer a catalog of defects present in individual cancers but do not discriminate between tumor-promoting genomic changes and those changes that arose incidentally during tumor progression. Functional studies are necessary to draw this distinction, and in many cancers the list of candidate genomic changes can be quite large. To parse through changes in gene copy number variation we use cross-species comparisons and functional studies with a conserved zebrafish melanoma model. Since some of the genomic changes involved in melanoma progression are seen in other cancers, our studies may provide broader insights into cancer development. The genetic changes we define may be useful as diagnostic and prognostic indicators of disease as well as therapeutic targets for melanoma and potentially other types of cancer. The two areas of study in this project are: 1. Define gene copy number changes that are shared between human and zebrafish melanomas, and use functional screening to identify new melanoma genes. Mechanisms of melanoma formation are conserved between zebrafish and humans. By determining genomic alterations common to zebrafish and human melanomas we can uncover new genes and mechanisms involved in melanomagenesis. 2. Examine the BMP-family ligand GDF6 for its roles in melanoma progression and melanocyte development. The comparative studies above have already identified an excellent candidate melanoma gene, GDF6. This BMP-family ligand is recurrently amplified and overexpressed in human and zebrafish melanomas, and its expression pattern during embryogenesis suggests a role in regulation of melanocyte development. We will assess how GDF6, and BMP signaling in general, participate in melanoma formation, perhaps by regulating the differentiation and proliferation of melanocytes.

Public Health Relevance

Melanoma is the most aggressive and deadliest skin cancer. Nearly 60,000 Americans and a much larger number of patients worldwide are diagnosed with this disease each year. As with other cancers, melanomas arise due to an accumulation of genomic defects that cause cells to proliferate without restraint. Many of the defects that contribute to melanoma are currently not known. In addition, while there has been recent progress in melanoma therapeutics, the advanced stages of this disease remain largely intractable. These studies will identify genomic abnormalities that promote melanoma progression and define their involvement in fundamental processes that regulate cell number. Knowledge of these defects will enhance our understanding of this disease and provide opportunities to advance melanoma diagnosis, prognosis and therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR063850-03
Application #
8862391
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Tseng, Hung H
Project Start
2013-07-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
Neto, Ana; Ceol, Craig J (2018) Melanoma-associated GRM3 variants dysregulate melanosome trafficking and cAMP signaling. Pigment Cell Melanoma Res 31:115-119
Venkatesan, Arvind M; Vyas, Rajesh; Gramann, Alec K et al. (2018) Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma. J Clin Invest 128:294-308
Kasheta, Melissa; Painter, Corrie A; Moore, Finola E et al. (2017) Identification and characterization of T reg-like cells in zebrafish. J Exp Med 214:3519-3530
Tang, Qin; Iyer, Sowmya; Lobbardi, Riadh et al. (2017) Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single-cell resolution using RNA sequencing. J Exp Med 214:2875-2887
Neiswender, James V; Kortum, Robert L; Bourque, Caitlin et al. (2017) KIT Suppresses BRAFV600E-Mutant Melanoma by Attenuating Oncogenic RAS/MAPK Signaling. Cancer Res 77:5820-5830
Wojciechowska, S; van Rooijen, E; Ceol, C et al. (2016) Generation and analysis of zebrafish melanoma models. Methods Cell Biol 134:531-49
Wojciechowska, Sonia; Zeng, Zhiqiang; Lister, James A et al. (2016) Melanoma Regression and Recurrence in Zebrafish. Methods Mol Biol 1451:143-53
Moore, Finola E; Garcia, Elaine G; Lobbardi, Riadh et al. (2016) Single-cell transcriptional analysis of normal, aberrant, and malignant hematopoiesis in zebrafish. J Exp Med 213:979-92
Ceol, Craig J; Houvras, Yariv (2016) Uncharted Waters: Zebrafish Cancer Models Navigate a Course for Oncogene Discovery. Adv Exp Med Biol 916:3-19
Iyengar, Sharanya; Kasheta, Melissa; Ceol, Craig J (2015) Poised Regeneration of Zebrafish Melanocytes Involves Direct Differentiation and Concurrent Replenishment of Tissue-Resident Progenitor Cells. Dev Cell 33:631-43

Showing the most recent 10 out of 11 publications