The spontaneous development of cutaneous melanomas in Tyr-Ras+ transgenic mice on INK4a +1- and INK4a-/- backgrounds established a causal role of activated RAS in the pathogenesis of melanoma. The requirement for continuous RAS activation to maintain the viability of established tumors in the inducible Tyr/Tet-Ras+ INK4a-/-system demonstrated a critical and essential role for activated RAS in maintenance of melanomas. However, this RAS-INK4a melanoma model fails to recapitulate an important hallmark of the human disease - metastasis. It is this 'deficiency' that renders the RAS-INK4a model uniquely suitable for the discovery, characterization and validation of metastasis pathways. In this proposal, we will generate of a novel melanoma model in which the candidate progression gene, Met, can be regulated somatically in established RAS-induced non-metastatic melanomas. The impact of MET activation (and deactivation) will be examined on phenotypic, molecular/genetic and genomic levels to validate a role for MET in progression, and ultimately to delineate genes and pathways critically important for tumor progression, and possibly metastasis

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093947-02
Application #
6620394
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mohla, Suresh
Project Start
2001-12-12
Project End
2006-11-30
Budget Start
2003-02-10
Budget End
2003-11-30
Support Year
2
Fiscal Year
2003
Total Cost
$356,631
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
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
Kwong, Lawrence N; Heffernan, Timothy P; Chin, Lynda (2013) A systems biology approach to personalizing therapeutic combinations. Cancer Discov 3:1339-44
Cheng, Christine S; Rai, Kunal; Garber, Manuel et al. (2013) Semiconductor-based DNA sequencing of histone modification states. Nat Commun 4:2672
Hodis, Eran; Watson, Ian R; Kryukov, Gregory V et al. (2012) A landscape of driver mutations in melanoma. Cell 150:251-63
Tsao, Hensin; Chin, Lynda; Garraway, Levi A et al. (2012) Melanoma: from mutations to medicine. Genes Dev 26:1131-55
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
Scott, Kenneth L; Chin, Lynda (2010) Signaling from the Golgi: mechanisms and models for Golgi phosphoprotein 3-mediated oncogenesis. Clin Cancer Res 16:2229-34
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
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

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