TGFbeta1 has both tumor suppressor and oncogenic roles in human cancer development, but the mechanisms underlying this switch in function remain elusive. Changing interactions of TGFbeta1 with oncogenic pathways that are activated in cancer cells such as ras may underlie this dual function. We have developed a transgenic mouse model that allows conditional regulation of both TGFbeta1 and oncogenic ras in the mouse epidermis. We find a synergistic induction of angiogenesis and epidermal disorganization by the combined expression of both pathways. Transcriptional profiling of this interaction in primary keratinocytes reveals antagonistic and synergistic responses that reflect both tumor suppression and tumor progression pathways. The central hypothesis of this research proposal is that during multistage carcinogenesis specific antagonistic and synergistic interactions occur between ras and TGFbeta signaling pathways that regulate the phenotype of the cancer cell. The first specific aim will test the hypothesis that coexpression of ras and TGFbeta1 leads to rapid malignancy and metastasis by examining inducing both transgenes in the normal epidermis and monitoring tumor development.
Specific Aim 2 examines the nature and mechanism of the rapid angiogenic response observed in the triple transgenic epidermis and tests the significance for tumor phenotypes observed in Specific Aim1.
Specific Aim 3 tests the hypothesis that ras and TGFbeta1 disrupt the normal structural integrity of the epidermis through altered matrix and junctional component expression.
Specific Aim 4 uses an in vitro primary keratinocyte model to examine how components of ras and TGFbeta1 signaling pathways interact to regulate gene expression associated with tumor suppression and tumor progression. The long-range goals of this research project are to understand the molecular basis of the interaction between ras and TGFbeta1 so that rational therapeutic strategies can be devised that block the synergistic prometastatic interactions of these pathways. Cancer in humans develops through from the stepwise activation and loss of signaling pathways that govern the behavior of the tumor cell, its interaction with neighboring cells, local microenvironment and organism. The TGFbeta1 and ras pathways are altered in many human cancers and synergistic interactions are important in metastases The long-range goals of this research project are to understand the molecular basis of the interaction between ras and TGFbeta1 so that rational therapeutic strategies can be devised that block the synergistic prometastatic interactions of these pathways. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122109-03
Application #
7440319
Study Section
Special Emphasis Panel (ZRG1-ONC-U (90))
Program Officer
Jhappan, Chamelli
Project Start
2006-08-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
3
Fiscal Year
2008
Total Cost
$240,628
Indirect Cost
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
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Zhu, B; Ferry, C H; Blazanin, N et al. (2014) PPAR?/? promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling. Oncogene 33:5348-59
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Mohammed, Javed; Gunderson, Andrew J; Khong, Hong-Hanh et al. (2013) TGF?1 overexpression by keratinocytes alters skin dendritic cell homeostasis and enhances contact hypersensitivity. J Invest Dermatol 133:135-43
Zhu, Bokai; Khozoie, Combiz; Bility, Moses T et al. (2012) Peroxisome proliferator-activated receptor ?/? cross talks with E2F and attenuates mitosis in HRAS-expressing cells. Mol Cell Biol 32:2065-82
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Mordasky Markell, Lauren; Pérez-Lorenzo, Rolando; Masiuk, Katelyn E et al. (2010) Use of a TGFbeta type I receptor inhibitor in mouse skin carcinogenesis reveals a dual role for TGFbeta signaling in tumor promotion and progression. Carcinogenesis 31:2127-35
Vijayachandra, Kinnimulki; Higgins, William; Lee, Jessica et al. (2009) Induction of p16ink4a and p19ARF by TGFbeta1 contributes to growth arrest and senescence response in mouse keratinocytes. Mol Carcinog 48:181-186
Bae, Dong-Soon; Blazanin, Nicholas; Licata, Mathew et al. (2009) Tumor suppressor and oncogene actions of TGFbeta1 occur early in skin carcinogenesis and are mediated by Smad3. Mol Carcinog 48:441-53

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