Transforming growth factor beta (TGFp) promotes epithelial differentiation and inhibits cell growth. Defects in TGFp signaling are common in cancer and frequently associated with reduced apoptosis and more aggressive tumor behavior. Though many TGFp signaling components function as tumor suppressors in breast, colon, and skin cancers, TGFp signaling in lung cancer is largely unexplored. My hypotheses are that defective TGFp signaling promotes tumor growth in LSCC and that specific TGFPsignaling defects are associated with distinct clinical tumor behavior and distinct tracheal epithelial cell behavior. I have observed frequent loss of TGFp signaling molecules in human LSCC samples.
In Aim 1 I will define the spectrum and consequences of TGFp signaling defects in human LSCC.
In Aim 2 I will use cultured tracheal epithelial cells to determine the effect of specific TGFp signaling defects on apoptosis, cell cycle arrest, migration, and endogenous TGFp production.
In Aim 3 I will create a novel mouse model of LSCC to examine TGFp signaling in vivo. In summary, these studies examine how TGFp signaling defects modulate behavior of airway epithelial cells in vivo and in vitro and how these changes promote the growth of LSCC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA131483-05
Application #
8320331
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2008-09-23
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$136,900
Indirect Cost
$9,400
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Malkoski, Stephen P; Cleaver, Timothy G; Thompson, Joshua J et al. (2014) Role of PTEN in basal cell derived lung carcinogenesis. Mol Carcinog 53:841-6
Malkoski, Stephen P; Haeger, Sarah M; Cleaver, Timothy G et al. (2012) Loss of transforming growth factor beta type II receptor increases aggressive tumor behavior and reduces survival in lung adenocarcinoma and squamous cell carcinoma. Clin Cancer Res 18:2173-83
Hudish, Tyler M; Opincariu, Laura I; Mozer, Anthony B et al. (2012) N-nitroso-tris-chloroethylurea induces premalignant squamous dysplasia in mice. Cancer Prev Res (Phila) 5:283-9
Malkoski, Stephen P; Wang, Xiao-Jing (2012) Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer. FEBS Lett 586:1984-92
Malkoski, Stephen P; Cleaver, Timothy G; Lu, Shi-Long et al. (2010) Keratin promoter based gene manipulation in the murine conducting airway. Int J Biol Sci 6:68-79
White, R A; Malkoski, S P; Wang, X-J (2010) TGFýý signaling in head and neck squamous cell carcinoma. Oncogene 29:5437-46