The long term goal is to identify molecular targets that can be used for prognosis and therapy of HNSCC. Head &neck squamous cell carcinomas (HNSCC) represent the 6th most common cancer type in western countries. The major HNSCC etiological factors are environmental carcinogens, e.g., tobacco and alcohol, which cause genetic alterations and chronic inflammation in head &neck (H&N) tissues. In this application, we will use an inducible H&N-specific gene targeting system to introduce several genetic alterations in the TGF? signaling pathway, which are common in human HNSCC, into mouse H&N tissues, and assess the mechanisms by which these alterations promote HNSCC development.
Aim 1 will examine molecular mechanisms of Smad4 loss-mediated HNSCC development. We will assess if any Fanc/Brca members are direct Smad4 transcriptional targets, and if VEGF overexpression in Smad4-/- HNSCCs is the result of Smad3 activation and contributes to Smad4 loss-mediated HNSCC carcinogenesis. Genome-wide analyses will be performed to identify additional alterations caused by Smad4 loss, which contribute to oncogenic effects on H&N epithelia and stroma.
Aim 2 will assess the role of Smad2 loss in HNSCC promotion. We will determine if Smad2 loss promotes HNSCC formation and progression in the presence of a Kras mutation. We will analyze if increased HGF signaling found in Smad2-/- tissues contributes to Smad2 loss-associated oncogenic effects and study the mechanisms of HGF upregulation in Smad2-/- cells. Genome-wide screens will also be performed to identify molecular alterations caused by Smad2 loss in H&N tissues.
Aim 3 will assess the role of stromal TGF?RII loss in HNSCC development. We will induce TGF?RII deletion in oral fibroblasts to ascertain if this will induce or promote HNSCC formation in the presence of either a chemical carcinogen-induced H-ras mutation or TGF?RII deletion in H&N epithelia. Pathological and molecular alterations caused by oral fibroblast TGF?RII deletion will be analyzed. These studies will not only improve our understanding of HNSCC biology, but will also directly test therapeutic approaches in HSNCC with specific TGF? signaling defects.
The application will use state-of-the-art experimental models and approaches to identify molecular mechanisms that cause head &neck cancer formation and progression. The proposed studies will lead to the identification of biomarkers that can be used to improve cancer prognosis and therapy.
|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|
|Mitra, Doyel; Fernandez, Pamela; Bian, Li et al. (2013) Smad4 loss in mouse keratinocytes leads to increased susceptibility to UV carcinogenesis with reduced Ercc1-mediated DNA repair. J Invest Dermatol 133:2609-16|
|White, Ruth A; Neiman, Jill M; Reddi, Anand et al. (2013) Epithelial stem cell mutations that promote squamous cell carcinoma metastasis. J Clin Invest 123:4390-404|
|Han, Gangwen; Bian, Li; Li, Fulun et al. (2013) Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis. Nat Med 19:421-8|
|Keysar, Stephen B; Le, Phuong N; Anderson, Ryan T et al. (2013) Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer. Cancer Res 73:3381-92|
|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|
|Han, Gangwen; Li, Fulun; Singh, Tej Pratap et al. (2012) The pro-inflammatory role of TGF?1: a paradox? Int J Biol Sci 8:228-35|
|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|
|Deng, Yu; Deng, Hui; Liu, Jing et al. (2012) Transcriptional down-regulation of Brca1 and E-cadherin by CtBP1 in breast cancer. Mol Carcinog 51:500-7|
|Weber, Stephen M; Bornstein, Sophia; Li, Yuexin et al. (2011) Tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induces AKT activation in head and neck epithelia. Int J Oncol 39:1193-8|
Showing the most recent 10 out of 23 publications