The overall objective of this project is the generation of inducible mouse models that closely mimic the development of human skin and head and neck cancers. My colleagues and I have recently developed inducible mouse models that allow the activation of oncogenes or inactivation of tumor suppressor genes in a restricted area of the skin, oral cavity or esophagus in stem cells that renew these stratified epithelia. Thus, we can create mice with discrete genetic changes in somatic cells that are identical to events that are thought to occur in human tumors. The genetic changes identified to date are primarily associated with early stages of tumor development. Much less is known about genetic changes that occur as tumors progress to metastatic lesions. Thus, our application will focus on recently discovered candidate genes implicated in promoting tumor progression through mechanisms that are both dependent on and independent of genomic instability. To identify novel genetic changes associated with tumor progression in our inducible mouse models, we will analyze tumors using both Affymetrix arrays and BAC/CGH arrays. In parallel studies, we will also analyze human skin and head and neck tumors which exhibit an aggressive nature and propensity to metastasize by Affymetrix arrays and BAC/CGH arrays and compare these findings with results obtained from analysis of the mouse tumors. Our inducible mouse models develop tumors as the result of discrete genetic changes, therefore these models are ideally suited to test novel drugs designed to interfere with specific gene products or signaling pathways. Pilot experiments will be performed to assess the utility of these models as tools for translational studies. Imaging will be utilized for the early detection of metastatic lesions in these studies and to monitor regression following treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA105491-01
Application #
6734369
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (J1))
Program Officer
Marks, Cheryl L
Project Start
2004-09-30
Project End
2009-03-31
Budget Start
2004-09-30
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$850,000
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Lee, Sangjun; Rodriguez-Villanueva, Julio; McDonnell, Timothy (2017) Restrained Terminal Differentiation and Sustained Stemness in Neonatal Skin by Ha-Ras and Bcl-2. Am J Dermatopathol 39:199-203
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Terzian, Tamara; Dumble, Melissa; Arbab, Farinaz et al. (2011) Rpl27a mutation in the sooty foot ataxia mouse phenocopies high p53 mouse models. J Pathol 224:540-52
Lauth, Matthias; Bergström, Asa; Shimokawa, Takashi et al. (2010) DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS. Nat Struct Mol Biol 17:718-25
Honeycutt, Kimberly A; Waikel, Rebekah L; Koster, Maranke I et al. (2010) The effect of c-myc on stem cell fate influences skin tumor phenotype. Mol Carcinog 49:315-9
Terzian, Tamara; Torchia, Enrique C; Dai, Daisy et al. (2010) p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation. Pigment Cell Melanoma Res 23:781-94
Jaks, Viljar; Kasper, Maria; Toftgard, Rune (2010) The hair follicle-a stem cell zoo. Exp Cell Res 316:1422-8

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