Tumor progression in colorectal cancer (CRC) involves accumulation of genetic and epigenetic changes 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) causing severe 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. In vivo, 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 through regulation 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 examine implied 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, whether this phenomenon is associated at any level with tumor type or outcome, and the significance at the molecular level with respect to cause and effect. Finally, in aim 3 we will use chemical genetics to interrogate 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 for Chemical 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.

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National Cancer Institute (NCI)
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Vanderbilt University Medical Center
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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
Weiss, Vivian L; Kiernan, Colleen; Wright, Jesse et al. (2018) Fine-Needle Aspiration-Based Grading of Pancreatic Neuroendocrine Neoplasms Using Ki-67: Is Accurate WHO Grading Possible on Cytologic Material? J Am Soc Cytopathol 7:154-459
Roberts, Jordan; Gonzalez, Raul S; Revetta, Frank et al. (2018) Mesenteric tumour deposits arising from small-intestine neuroendocrine tumours are frequently associated with fibrosis and IgG4-expressing plasma cells. Histopathology 73:795-800
Gibson, William E; Gonzalez, Raul S; Cates, Justin M M et al. (2018) Hepatic micrometastases are associated with poor prognosis in patients with liver metastases from neuroendocrine tumors of the digestive tract. Hum Pathol 79:109-115
Fenix, Aidan M; Neininger, Abigail C; Taneja, Nilay et al. (2018) Muscle-specific stress fibers give rise to sarcomeres in cardiomyocytes. Elife 7:
Wang, Jing; Zhao, Yue; Zhou, Xiaofan et al. (2018) Nascent RNA sequencing analysis provides insights into enhancer-mediated gene regulation. BMC Genomics 19:633
Burns, Michael C; Howes, Jennifer E; Sun, Qi et al. (2018) High-throughput screening identifies small molecules that bind to the RAS:SOS:RAS complex and perturb RAS signaling. Anal Biochem 548:44-52
Herring, Charles A; Banerjee, Amrita; McKinley, Eliot T et al. (2018) Unsupervised Trajectory Analysis of Single-Cell RNA-Seq and Imaging Data Reveals Alternative Tuft Cell Origins in the Gut. Cell Syst 6:37-51.e9

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