The significance and impact of melanoma as a disease entity can not be understated. Despite the long history of clinical and molecular efforts directed towards this disease, surprisingly little is known about the precise genetic lesions leading to melanoma and even less is known with regard to how these few genetic lesions relate to disease classification or progression. Significant progress on both the basic and clinical fronts could be achieved through the production of an accurate mouse model of malignant melanoma that faithfully reproduces disease progression on the pathological and molecular levels. This proposal attempts to refine and validate further an established mouse model of cutaneous melanoma. To achieve this goal, mice will be engineered to possess several genetic lesions commonly observed in human melanomas, including activated MET, EGF receptors as well as disruption of the p16INK4a, PTEN and possibly Mxi1 genes. Evolving gene expression patterns and genomic changes at various tumor stages will be extensively cataloged as a means of validation. This refined model of melanoma should serve to advance our understanding of melanoma biology as well as to provide a system for melanoma gene discovery. The latter will include a combination of CGH, genome wide LOH, genetic mapping of susceptibility loci and candidate gene mutational analyses. The use of these melanoma mice in preclinical testing are outlined as well.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA084313-04
Application #
6514297
Study Section
Special Emphasis Panel (ZCA1-SRRB-7 (O3))
Program Officer
Marks, Cheryl L
Project Start
1999-09-30
Project End
2004-03-31
Budget Start
2002-04-22
Budget End
2003-03-31
Support Year
4
Fiscal Year
2002
Total Cost
$839,220
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
Wardwell-Ozgo, J; Dogruluk, T; Gifford, A et al. (2014) HOXA1 drives melanoma tumor growth and metastasis and elicits an invasion gene expression signature that prognosticates clinical outcome. Oncogene 33:1017-26
Kapoor, Avnish; Yao, Wantong; Ying, Haoqiang et al. (2014) Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158:185-197
Hu, Jian; Ho, Allen L; Yuan, Liang et al. (2013) From the Cover: Neutralization of terminal differentiation in gliomagenesis. Proc Natl Acad Sci U S A 110:14520-7
Dunn, Gavin P; Rinne, Mikael L; Wykosky, Jill et al. (2012) Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev 26:756-84
Scott, Kenneth L; Nogueira, Cristina; Heffernan, Timothy P et al. (2011) Proinvasion metastasis drivers in early-stage melanoma are oncogenes. Cancer Cell 20:92-103
Ding, Zhihu; Wu, Chang-Jiun; Chu, Gerald C et al. (2011) SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470:269-73
Nogueira, C; Kim, K-H; Sung, H et al. (2010) Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis. Oncogene 29:6222-32
Sahin, Ergün; Depinho, Ronald A (2010) Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464:520-8
Kabbarah, Omar; Nogueira, Cristina; Feng, Bin et al. (2010) Integrative genome comparison of primary and metastatic melanomas. PLoS One 5:e10770
Zheng, Bin; Jeong, Joseph H; Asara, John M et al. (2009) Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell 33:237-47

Showing the most recent 10 out of 51 publications