The SPORE in GI Cancer: Research: Projects

Project 3: Understanding and Controlling p120 Dysfunction in Colorectal Cancer

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-defi cient CRCs, p120 localizes aberrantly to the cytoplasm, and both E-cadherin-loss and cytoplasmic p120 are tightly associated with metastasis and poor prognosis. p120 itself is downregulated in a subset of CRC but the significance is not yet clear. We have found that p120 is essential for E-cadherin retention at the cell surface. p120 ablation in vitro and in vivo destabilizes and/or eliminates E-cadherin (and associated catenins) causing severe defects in cell morphology and adhesion. In addition, we have found that cadherin-association is required for p120-dependant regulation of Rho by a novel mechanism that may directly mediate contact-dependent inhibition. Interestingly, in vitro p120-ablation in various cell types induces constitutive activation of Rho, cell growth in the absence of serum, and loss of contact inhibition. Moreover, the same or similar pathways in vivo appear to mediate activation of a ROCK/NFkB/COX-2 signaling cascade and chronic inflammation. These observations reveal novel co-dependent interactions between p120 and E- cadherin that are likely required for contact inhibition, suppression of metastasis, and control of inflammation. Our progress report describes these observations, along with preliminary data based on a novel mouse model for limited conditional p120-ablation in the small intestine and colon. The aims below seek to apply these observations to tumor progression and clinical intervention in human CRC.

Aim 1: To evaluate pharmaceutical blockade of signaling pathways activated by p120 and/or E-cadherin dysfunction as targets for suppression of tumor progression or metastasis.

Aim 2: To determine the pattern and signifi cance of observed defects in p120 protein and mRNA expression as they pertain to CRC type and tumor progression.

Aim 3: To Identify by high throughput screening (HTS) novel compounds that reverse p120-dependent defects in E-cadherin activity.

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