Tumor progression in colorectal cancer (CRC) involves accumulation of genetic and epigeneticchanges that ultimately lead to malignancy. E-cadherin downregulation occurs frequently and is widely believed to be a pivotal event in the transition to metastasis. In the majority of E-cadherin-deficient CRCs, p120 localizes aberrantly to the cytoplasm, and E-cadherin-loss / cytoplasmic p120 is strongly associated poor prognosis. p120 itself is downregulated in a subset of CRC but the significance is not yet clear. We have found that p120 ablation in vitro and in vivo destabilizes E-cadherin (and associated catenins) causingsevere defects in cell morphology and adhesion. Interestingly, in vitro p120-ablation in many cell types induces constitutive activation of Rho, cell growth in the absence of serum, and loss of contact inhibition. Invivo, similar effects lead to cell autonomous activation of a ROCK/NFKB/COX-2 signaling cascade and chronic inflammation, an observation of potential relevance to the efficacy of NSAIDS and COX-2 inhibitors in CRC. Our data suggest novel co-dependent interactions between p120 and E-cadherin that act throughregulation of Rho to suppress metastasis and inflammation. The progress report describes these effects, along with a novel molecular explanation for the relationship between Rho, p120, and E-cadherin.
The aims (below) seek to apply our findings to tumor progression and clinical intervention in CRC.
In aim 1, we will evaluate a simplified p120 KO mouse model to ascertain whether pharmaceutical intervention at the level of pathways activated by p120 (or E-cadherin) downregulation can suppress tumor progression, tumor growth,or metastasis.
Aim 2 explores two separate hypotheses based on novel observations. First, to examineimplied relationships between p120 loss, mismatch repair (MMR) deficient CRC, and defects in TGF0IIR signaling, we will perform a head-to-head comparison between well-annotated groups of MMR-deficient and proficient tumors. Second, we will follow up on novel observations of p120 downregulation at the mRNA level in advanced CRC. We will determine whether mRNA levels fall at early stages of CRC progression, whetherthis phenomenon is associated at any level with tumor type or outcome, and the significance at themolecular level with respect to cause and effect. Finally, in aim 3 we will use chemical genetics tointerrogate a well characterized but as yet unknown signaling pathway associated with p120-dependant inactivation of E-cadherin. In collaboration with the Beauchamp lab (project 2) and the Vanderbilt Institute forChemical Biology (VICB) high throughput screening facility, we have developed a high throughput small molecule screen (HTS) to identify novel compounds that rescue E-cadherin function in CRC model cell lines.The application of HTS represents an innovative approach to delineating signaling pathways that control p1207E-cadherin function, and could lead to identification of novel compounds capable of suppressing tumor progression or metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA095103-06
Application #
7245694
Study Section
Special Emphasis Panel (ZCA1-GRB-I (J1))
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2007-07-25
Budget End
2008-04-30
Support Year
6
Fiscal Year
2007
Total Cost
$259,103
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Herring, Charles A; Chen, Bob; McKinley, Eliot T et al. (2018) Single-Cell Computational Strategies for Lineage Reconstruction in Tissue Systems. Cell Mol Gastroenterol Hepatol 5:539-548
Choi, Eunyoung; Lantz, Tyler L; Vlacich, Gregory et al. (2018) Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. Gut 67:1595-1605
Singh, Kshipra; Coburn, Lori A; Asim, Mohammad et al. (2018) Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses. Cancer Res 78:4303-4315
Idrees, Kamran; Padmanabhan, Chandrasekhar; Liu, Eric et al. (2018) Frequent BRAF mutations suggest a novel oncogenic driver in colonic neuroendocrine carcinoma. J Surg Oncol 117:284-289
Zhang, Qin; Jeppesen, Dennis K; Higginbotham, James N et al. (2018) Mutant KRAS Exosomes Alter the Metabolic State of Recipient Colonic Epithelial Cells. Cell Mol Gastroenterol Hepatol 5:627-629.e6
Choksi, Yash A; Reddy, Vishruth K; Singh, Kshipra et al. (2018) BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability. Mucosal Immunol 11:1363-1374
Saito-Diaz, Kenyi; Benchabane, Hassina; Tiwari, Ajit et al. (2018) APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway. Dev Cell 44:566-581.e8
Davenport, James R; Su, Timothy; Zhao, Zhiguo et al. (2018) Modifiable lifestyle factors associated with risk of sessile serrated polyps, conventional adenomas and hyperplastic polyps. Gut 67:456-465
Liu, Qi; Herring, Charles A; Sheng, Quanhu et al. (2018) Quantitative assessment of cell population diversity in single-cell landscapes. PLoS Biol 16:e2006687
Means, Anna L; Freeman, Tanner J; Zhu, Jing et al. (2018) Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer. Cell Mol Gastroenterol Hepatol 6:257-276

Showing the most recent 10 out of 447 publications