Cutaneous malignant melanoma (CMM) is the most lethal form of skin cancer, and its incidence has been increasing at an alarming rate in the U.S. and around the world. Exposure to damaging ultraviolet radiation (UVR) is clearly a risk factor for the disease, borne out by the recent linkage between tanning bed usage and dramatically increased melanoma incidence in young females. Better understanding of the mechanisms by which CMM progresses to metastatic forms is likely to provide important new therapeutic approaches for improving survival rates. The study of metastasis suppressor genes, such as NM23-H1 (NM23-M1 in mouse), has provided new insights into molecular mechanisms underlying melanoma metastasis. This application builds on our novel observations that NM23-H1 is a 3'-5'exonuclease which exerts proofreading activity on DNA in vitro, that its 3'-5'exonuclease activity is required for metastasis suppressor function, and that the protein promotes repair of UVR-induced lesions in DNA. In addition, transgenic mouse models developed for this project recapitulate for the first time the metastasis suppressor function of NM23-H1 in UVR-induced CMM. Our findings support a model in which loss of NM23-H1 expression results in compromised genomic integrity and mutations that drive malignant progression in CMM.
In Specific Aim 1, the contributions of NM23-M1 and NM23-M2 to UV radiation-induced metastatic melanoma will be determined in transgenic mouse strains deficient in expression of one, or both, of the isoforms.
In Specific Aim 2, the molecular mechanisms underlying promotion of DNA repair pathways by NM23 proteins will be elucidated, and the impact of perturbing those pathways on metastasis suppressor activity assessed in cell culture and tumor cell explanation model systems.
Specific Aim 3 will apply the powerful technologies of massively parallel sequencing for whole genome sequencing and RNA-seq to primary and metastatic melanomas to identify candidate metastasis-driving genomic alterations and gene expression profiles. The proposed studies will provide the first systematic analysis of specific DNA repair and related pathways through which a metastasis suppressor gene opposes malignant progression, as well as the first application of a transgenic mouse model to the study of metastasis suppressor function in CMM. Our studies should provide novel and critical insights that can be pursued to combat melanoma in its advanced and lethal forms.

Public Health Relevance

While cutaneous malignant melanoma (CMM) is treated surgically with some success in its early stages, conventional treatments are ineffective once the disease has spread, or metastasized, to distant organs. This application is directed to elucidating the mechanisms that underlie metastasis in CMM, particularly that caused by overexposure to damaging ultraviolet radiation. These studies have considerable potential to improve diagnosis and prognosis of CMM patients, and to provide novel insights for effective treatments of the disease in its most advanced and lethal stages.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA159871-02
Application #
8542790
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Okano, Paul
Project Start
2012-09-10
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$455,663
Indirect Cost
$113,539
Name
University of Maryland Baltimore
Department
Biochemistry
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Puts, Gemma S; Leonard, M Kathryn; Pamidimukkala, Nidhi V et al. (2018) Nuclear functions of NME proteins. Lab Invest 98:211-218
Leonard, M Kathryn; McCorkle, Joseph R; Snyder, Devin E et al. (2018) Identification of a gene expression signature associated with the metastasis suppressor function of NME1: prognostic value in human melanoma. Lab Invest 98:327-338
Tarasen, Ashley; Carlson, J Andrew; Leonard, M Kathryn et al. (2017) Pigmented Epithelioid Melanocytoma (PEM)/Animal Type Melanoma (ATM): Quest for an Origin. Report of One Unusual Case Indicating Follicular Origin and Another Arising in an Intradermal Nevus. Int J Mol Sci 18:
Leonard, M Kathryn; Pamidimukkala, Nidhi; Puts, Gemma S et al. (2017) The HGF/SF Mouse Model of UV-Induced Melanoma as an In Vivo Sensor for Metastasis-Regulating Gene. Int J Mol Sci 18:
Khatri, Raju; Arad, Michal; Ortlip, Timothy et al. (2017) Harvesting multipotent progenitor cells from a small sample of tonsillar biopsy for clinical applications. Stem Cell Res Ther 8:174
Fisher, Matthew L; Adhikary, Gautam; Grun, Dan et al. (2016) The Ezh2 polycomb group protein drives an aggressive phenotype in melanoma cancer stem cells and is a target of diet derived sulforaphane. Mol Carcinog 55:2024-2036
Novak, Marián; Leonard, Mary Kathryn; Yang, Xiuwei H et al. (2015) Metastasis suppressor NME1 regulates melanoma cell morphology, self-adhesion and motility via induction of fibronectin expression. Exp Dermatol 24:455-61
Kaetzel, David M; Leonard, Mary K; Cook, Gemma S et al. (2015) Dual functions of NME1 in suppression of cell motility and enhancement of genomic stability in melanoma. Naunyn Schmiedebergs Arch Pharmacol 388:199-206
Fiore, Leann S; Ganguly, Sourik S; Sledziona, James et al. (2014) c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer. Oncogene 33:4508-4520
Baldwin, Lauren A; Hoff, John T; Lefringhouse, Jason et al. (2014) CD151-?3?1 integrin complexes suppress ovarian tumor growth by repressing slug-mediated EMT and canonical Wnt signaling. Oncotarget 5:12203-17

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