The study of epithelial to mesenchymal transition (EMT) and its regulation has great significance to understanding mechanisms that control tumor cell aggressiveness and metastasis. Important changes occur in cellular responses to external signals when cells are neoplastically transformed by potent oncoproteins such as Ras, and this may result in collaborative effects that push the phenotype toward aggressive tumor behavior. This application seeks to explore the mechanisms underlying the transition of tumor cells from a benign to a malignant phenotype. A clear understanding of the mechanisms behind these processes will provide avenues to more selective therapeutic interventions for the prevention of metastasis from primary tumors. Exploration of these areas also holds promise for the identification of more sensitive and specific biomarkers that may be predictive of cancer patient outcome. Our Central hypothesis is as follows: EMT is a critical and potentially reversible step in the acquisition of the metastatic phenotype in carcinoma. Improved understanding of the regulators of EMT may lead to novel biomarkers or novel molecular targets for cancer therapy. We and others have demonstrated that the Smad4 protein is a key regulator in these processes. Specific sub-hypotheses for each aim relate to this central hypothesis regarding the role of Smad4 in EMT and provide the basis for hypothesis-testing experiments.
Aim 1) Determine the mechanisms by which Ras cooperates with Transforming Growth Factor-beta (TGF-ft) to promote EMT and tumor progression. Hypothesis: Ras transformation of intestinal epithelial cells sets the stage for effective EMT induction by TGF-J3. We will test whether the combined effects of Ras + TGF-P exert their effect via (1 A) altered BMP signaling, or through the production of EGF ligands (1B).
Aim 2) Determine the TGF-[}-independent mechanism of Smad4 action in cancer cell EMT. Hypothesis: Smad4 is a critical modulator of EMT that functions in TGF-P independent cell regulation. We will test the whether Smad4 exerts its effects via (2A) regulation of the tight junction protein, claudin-1, through changes in claudin-1 gene expression (2B) or by (2C) restoration of BMP signaling. The clinical relevance of our findings will be explored in 2D.
Aim 3) Determine whether gene expression differences between Smad4 deficient colorectal cancer cells and their Smad4 expressing clones predict a set of regulatory factors critical to EMT and the metastatic phenotype. Given the importance of Smad4 as a tumor suppressor and our preliminary observations that it has important roles independent of TGF-p, we will use a gene expression microarray approach to identify gene expression differences that are associated with the phenotypic response to Smad4 expression that occur independently of TGF-p signaling. Hypothesis: Smad4 mediated EMT reversion is associated with altered gene expression patterns that are linked to mechanisms underlying EMT and metastasis. We will test for differences in expression profiles in human colon cancer cells transfected with Smad4 (3A) and validate the findings of microarray at mRNA and protein levels and determine the roles of selected targets in the phenotypic response to Smad4 expression (3B).
|Bhat, A A; Pope, J L; Smith, J J et al. (2015) Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis. Oncogene 34:4570-80|
|Pope, Jillian L; Bhat, Ajaz A; Sharma, Ashok et al. (2014) Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling. Gut 63:622-34|
|Shi, Chanjuan; Washington, M Kay; Chaturvedi, Rupesh et al. (2014) Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage-stellate cell interaction. Lab Invest 94:409-21|
|Hansen, Amanda G; Freeman, Tanner J; Arnold, Shanna A et al. (2013) Elevated ALCAM shedding in colorectal cancer correlates with poor patient outcome. Cancer Res 73:2955-64|
|Zhu, Jing; Wang, Jing; Shi, Zhiao et al. (2013) Deciphering genomic alterations in colorectal cancer through transcriptional subtype-based network analysis. PLoS One 8:e79282|
|Al-Greene, Nicole T; Means, Anna L; Lu, Pengcheng et al. (2013) Four jointed box 1 promotes angiogenesis and is associated with poor patient survival in colorectal carcinoma. PLoS One 8:e69660|
|Hanson, Alison J; Wallace, Heather A; Freeman, Tanner J et al. (2012) XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling. Mol Cell 45:619-28|
|Barrett, Caitlyn W; Smith, J Joshua; Lu, Lauren C et al. (2012) Kaiso directs the transcriptional corepressor MTG16 to the Kaiso binding site in target promoters. PLoS One 7:e51205|
|Freeman, Tanner J; Smith, J Joshua; Chen, Xi et al. (2012) Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of Î²-catenin. Gastroenterology 142:562-571.e2|
|Shi, Mingguang; Beauchamp, R Daniel; Zhang, Bing (2012) A network-based gene expression signature informs prognosis and treatment for colorectal cancer patients. PLoS One 7:e41292|
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