We have recently found that primary melanomas on the palms and soles arise from a field of histologically normal but genetically abnormal melanocytes surrounding the tumors. The genetic abnormalities in the 'field cells' are present in the in situ and invasive portions of the tumor. Thus the field cells are a subtle precursor of melanoma in situ, and are a possible source of local recurrence in melanoma since they are not detectable by current methods, and may extend outside the empirically-determined excision margins used in clinical practice (Bastian et al., 2000a). The evidence for this in acral melanomas is very strong. Improved understanding of the mechanism of the local recurrence in other types of melanoma would have significant clinical impact. Lentigo maligna melanoma (LMM) is a form of melanoma it shares with acral melanoma its histological growth pattern and risk of recurrence. We have found evidence for the existence of field cells in LMM, and hypothesize that they can cause recurrences when present at the margin. We will test this hypothesis by identifying DNA copy number changes in the invasive components of LMM using array CGH and look for their presence in the normal appearing melanocytes surrounding these tumors using FISH. We will determine whether the presence of field cells at the surgical margins is predictive of local recurrence. A critical question relates to the initial genetic events that permit the clonal growth of abnormal melanocytes out of which the tumor eventually develops. LMM arises on the chronically sun-exposed skin of elderly individuals. LMM incidence is significantly increased in individuals with xeroderma pigmentosum (XP). Our preliminary data indicates frequent deletions in genomic regions harboring DNA repair genes in LMM. We hypothesize that in LMM one of the earliest events causes a defect in the response to Uv-induced DNA. We will analyze genomic DNA of LMMs for recurrent aberrations of genomic regions harboring UV response genes. Candidate genes within these regions will undergo a mutational analysis for the detection of acquired or inherited sequence variations. UV response genes found to be altered in LMMs will be functionally evaluated in vitro and in vivo using xenografted artificial human skin reconstructs exposed to UV light. The long-term goals of this project is the understanding of the genetic progression of LMM and the identification of markers that improve the detection of minimal residual melanoma and current recommendations for safety margins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA025874-26
Application #
7310905
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
26
Fiscal Year
2006
Total Cost
$317,133
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Perego, M; Maurer, M; Wang, J X et al. (2018) A slow-cycling subpopulation of melanoma cells with highly invasive properties. Oncogene 37:302-312
Heppt, Markus V; Wang, Joshua X; Hristova, Denitsa M et al. (2018) MSX1-Induced Neural Crest-Like Reprogramming Promotes Melanoma Progression. J Invest Dermatol 138:141-149
Ca├▒adas, Israel; Thummalapalli, Rohit; Kim, Jong Wook et al. (2018) Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med 24:1143-1150
Jenkins, Russell W; Aref, Amir R; Lizotte, Patrick H et al. (2018) Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discov 8:196-215
Liu, Shujing; Zhang, Gao; Guo, Jianping et al. (2018) Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis. Nat Commun 9:5426
Reyes-Uribe, Patricia; Adrianzen-Ruesta, Maria Paz; Deng, Zhong et al. (2018) Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. Oncogene 37:4058-4072
Chen, Gang; Huang, Alexander C; Zhang, Wei et al. (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382-386
Vitiello, Marianna; Tuccoli, Andrea; D'Aurizio, Romina et al. (2017) Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells. Oncotarget 8:25395-25417
Krepler, Clemens; Sproesser, Katrin; Brafford, Patricia et al. (2017) A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma. Cell Rep 21:1953-1967
Somasundaram, Rajasekharan; Zhang, Gao; Fukunaga-Kalabis, Mizuho et al. (2017) Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. Nat Commun 8:607

Showing the most recent 10 out of 382 publications