|Institution||College of Medicine|
|Address||500 University Drive Hershey PA 17033|
Assistant Professor of Pathology, Pharmacology, and Biochemistry & Molecular Biology
Medical Director, Morphologic and Molecular Core Research Laboratory
SECONDARY APPOINTMENT(S)/ INSTITUTE(S)/ CENTER(S):
Pharmacology, Penn State Hershey Cancer Institute
GRADUATE PROGRAM AFFILIATIONS:
Ph.D., University of Pennsylvania, 2004
Postdoctoral Training, University of Pennsylvania, 2005-2010
The worldwide prevalence of esophageal cancer varies greatly with the highest rates found in Asia. In the United States the two most common types of esophageal cancers are squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). In 2010 there were about 16,600 new cases of esophageal cancer diagnosed in the US and approximately 14,500 deaths will occur from esophageal cancer. In fact, since patients are typically diagnosed at a late stage of the disease, overall five year survival is approximately 18%. Given the poor survival rate, the advanced stage of the disease at diagnosis and the increasing frequency of ESCC (worldwide) and EAC (US), it is increasingly important to understand the molecular mechanisms of initiation of these tumors as well as the genes and pathways involved.
ESCC is highlighted by the interplay of classical oncogenes and tumor suppressor genes. We have found that p120ctn, a tumor suppressor gene, is mislocalized to the cytoplasm or lost in nearly all human ESCC. This initial observation has been pursued in a genetically engineered mouse model through tissue-specific ablation of p120ctn, resulting in inflammation and cancer in the esophagus. Loss of p120ctn in the mouse esophagus results in tumor development that is nearly indistinguishable from human ESCC. Analyses of the development of these tumors in the mouse had revealed an important role for the immune system. The presence of immune cells in the tumor microenvironment is necessary for invasion of the epithelium and the activation of fibroblasts in the tumor microenvironment. The recruitment of these cells is dependent on NFkB activation in the epithelium, subsequent to p120ctn loss. The mechanism of NFkB activation is an area of current research in the laboratory. By identifying the processes by which NFkB signaling is activated we hope to identify potential therapeutic targets for ESCC. To that end, we employ two-dimensional as well as three-dimensional culturing techniques to dissect cellular crosstalk pathways. These in vitro experiments compliment in vivo experiments involving xenograft and genetically engineered mouse models of esophageal cancer.
Barrett’s esophagus (BE) is a highly prevalent premalignant condition whereby the normal stratified squamous esophageal epithelium undergoes a transdifferentiation process resulting in a simple columnar epithelium reminiscent of the small intestine. Barrett’s esophagus is a precursor lesion to esophageal adenocarcinoma (EAC), which has the highest rate of increase in incidence of any cancer type in the United States. Changes in BE are associated with epithelial exposure to acid and bile salts as a result of gastroesophageal reflux disease (GERD). Despite this well-defined epidemiologic association between acid reflux and BE, the genetic changes that induce this transdifferentiation process in esophageal keratinocytes are poorly defined. Our previous work has begun to identify pathways capable of inducing this transdifferentiation process. Having identified the transcription factors c-myc and Cdx1 as inducers of Barrett’s esophagus, we now wish to identify genes and biomarkers for the progression of BE to EAC.
This will be accomplished in a collaborative effort with GI surgeons providing surgical samples for our research. Our goals will be to establish new cell lines of BE and EAC, define the molecular and genetic changes between BE and EAC and to select and test candidate genes for their ability to mark those cells that are poised to develop into EAC before they undergo transformation. In a similar manner we will identify those genes and signaling pathways that are involved in the transformation process. Ultimately, these data will allow for biomarker development to predict the risk a Barrett’s esophagus patient has to develop EAC. As well, this research will allow for the development of targeted therapeutics for the treatment of EAC
Current and Possible Future Research Projects:
Identify the factors involved in NFkB activation
Understand the intercellular mechanisms by which p120ctn loss leads to transformation
Explore novel mouse models of esophageal cancer
Identify biomarkers for the progression of Barrett’s esophagus to Esophageal Adenocarcinoma
Identify pathways involved in the development of Esophageal Adenocarcinoma amenable to therapeutic intervention
These projects will be explored using genetic modeling in tissue culture and mouse model systems combined with biochemical, pharmacologic and cell & molecular biology techniques.
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