Description of Research Expertise

Research Interests

1. Regulation of beta-catenin transcriptional and cell-cell adhesion activity in intestinal epithelial cells.
2. Mechanisms of intestinal metaplasia of the esophagus and stomach
3. Role of the intestine-specific transcription factor Cdx2 in promoting intestinal stem cell identity
4. Coordination of differentiation and proliferation in the intestinal crypt and its dysregulation in carcinogenesis.
5. Mechanisms of cell-cell adhesion, and their role in intestinal epithelial cell differentiation, morphology, and carcinogenesis.


Description of Research

Intestinal Focus:

Colon cancer is an important cause of cancer mortality. In the United States, over 150,000 people are newly diagnosed with this disease each year, and a third of them will ultimately die from their disease. Beta-catenin is a multifunctional protein with known roles in enhancing proliferation, inhibiting intestinal cell differentiation and apoptosis, and regulating cell-cell adhesion, angiogenesis, and cell migration. Abnormal regulation of beta-catenin levels and function commonly occurs during colon carcinogenesis.

Dysregulation of beta-catenin endows cancer cells with many of the features necessary for colon carcinogenesis. The mechanisms by which normal intestinal cells regulate beta-catenin function, and by which cancer cells abrogate this regulation, are not understood.
The homeodomain transcription factor Cdx2 is a well-studied regulator of intestine-specific gene expression. It's role in promoting intestinal cell differentiation and regulating proliferation is recognized but the mechanism remains unknown. Our research has specifically investigated these processes.

We found that expression of Cdx2 inhibited beta-catenin/TCF transcriptional activity. In addition, we have developed a cell culture system to model Cdx2 induction of a polarized, columnar cell morphology in human colonocytes. This effect requires a functioning E-cadherin/beta-catenin complex, and involves post-translation modifications of beta-catenin. Current research is focused on characterizing the proliferation and cell-adhesion effects of Cdx2 on intestinal epithelial and cancer cells. Specifically we are testing the following hypothesis: Cdx2 inhibits colonocyte proliferation and promotes morphologic maturation by modulating beta-catenin transcriptional and cell-cell adhesion activity.

Our work therefore explores a possible role for Cdx2 in regulating the interdependent processes of cell-cell adhesion, acquisition of a polarized and columnar morphology, and cell-proliferation within the colonocyte.
Understanding these mechanisms will greatly improve our knowledge of the events occurring normally in colonic crypts as well as enhance our understanding of the events leading to dysregulation of proliferation and differentiation in human colon cancers.


Barrett’s Esophagus Focus:
Esophageal adenocarcinoma (EAC) has been the fastest rising malignancy in the U.S.. Several conditions increase the risk for the development of EAC, including obesity, smoking, diet, acid reflux, and, most significantly, Barrett's esophagus (BE). BE occurs at the gastroesophageal (GE) junction and is the replacement of normal squamous esophageal mucosa with an intestinalized columnar epithelium. It typically arises in response to chronic acid exposure and is associated with acid reflux. Importantly, the molecular mechanisms underpinning the establishment of Barrett's metaplasia are not understood. Moreover, no experimental cell-culture or animal models exist for this condition. Ectopic expression of intestine-specific transcription factors is characteristic of BE. The homeodomain transcription factor Cdx2 is an important regulator of intestine-specific gene expression. It is expressed ectopically in BE, but its role is unknown. Our research has investigated this role. We hypothesize that ectopic Cdx2 expression synergizes with acid reflux, COX-2 overexpression, tumor-suppressor p53 mutations, and/or alterations in DNA methylation patterns to reprogram the keratinocyte cells to promote intestinal transdifferentiation. We will test this hypothesis by developing cell-culture and transgenic mouse models for intestinal metaplasia.

Intestinal Stem Cell Focus:
Stem cells are defined by the capacity for long-term self-renewal and multilineage differentiation. Until relatively recently, our understanding of stem cell biology, as well as their role in many human disease processes from aging to cancer, has been rather limited. Moreover, interest in harnessing the stem cell’s capacity for self-renewal to promote organ and tissue regeneration cuts across many medical disciplines. Recently, genetic studies have identified several robust markers for stem cell populations in the intestine. These advances now make it possible to isolate stem cell populations for more advanced molecular investigations. One important challenge encountered by stem cells is to correctly determine their tissue identity based on environmental cues. Errors in stem cell identity are encountered in intestinal metaplasias of the esophagus and stomach, as well as many gastrointestinal cancers. We are exploring how the homeodomain transcription factor Cdx2 specifies the stem cell’s “intestinal” identity, both in the normal intestine as well as intestinal metaplasias The goal of this work is to better understand the molecular events that support and specify intestinal stem cells. Understanding these molecular processes will greatly improve our ability to develop novel therapeutic strategies to exploit the regenerative potential of stem cells, as well as correct stem cell errors and deficiencies that contribute to many human disease processes.


Lab personnel:
Mary Ann Crissey--Research Specialist and Lab Manager
Jianping Kong PhD--Post Doc