B. Mark Evers, M.D.

B. Mark Evers, M.D.
Professor, Department of Surgery
Director, UTMB Cancer Center
Director, Sealy Center for Cancer Cell Biology
Robertson-Poth Distinguished Chair & Professor in General Surgery
email: mevers@utmb.edu

Our laboratory is intensely focused on the evaluation of cellular mechanisms leading to the differentiation of the developing intestine and the growth of normal and neoplastic GI tissues. In addition, the developmental pattern of gene expression in the gut is also a specific area of interest using the human neurotensin gene which is expressed in the gut in a strict spatial and temporal pattern and then re-expressed in various colon cancers. We have identified cis-acting elements that are responsible for high-level neurotensin gene expression in the gut and postulate that a better understanding of the developmental and age-related changes in neurotensin gene expression will provide a better understanding of the specific cellular mechanisms regulating neurotensin-induced proliferation of gut mucosa. Novel mechanisms regulating neurotensin gene expression have been identified which include Ras activation, promoter methylation and the combinatorial effect of transcription factors acting on critical proximal elements. Current studies are assessing signaling pathways regulating neurotensin function as well as mechanisms for neurotensin secretion from intestinal endocrine cells. A recent genomic analysis identified multiple downstream targets of neurotensin including activation of members of the TGF-b signaling pathway as well as MAPK and NF-kB. Ongoing studies are currently evaluating the role of these signaling pathways in mediating the effect of neurotensin in normal and neoplastic tissues. From our studies, the neurotensin gene provides an important endocrine model to better delineate the complex mechanisms leading to differentiation of the gut to a small bowel or colonic phenotype and, in addition, provides a unique paradigm to further investigate the factors regulating the establishment and maintenance of certain cell lineage specific patterns along the cephalocaudal axis of the gut.

Another area of active interest in the laboratory is the better understanding of the signaling pathways which contribute to intestinal cell differentiation. Our laboratory has examined, in particular, downstream effectors of the Ras signaling pathway. Current work has identified a critical role for the PI3-K /PTEN pathway in regulating intestinal cell differentiation and downstream targets which include the homeobox gene Cdx-2 and TRAIL, a novel member of the TNF family. These studies provide a clearer understanding of the crucial signaling mechanisms that contribute to intestinal homeostasis and may provide for novel therapeutic strategies in the treatment of gut neoplasias.

Finally, our laboratory is alsoassessing mechanisms leading to pancreatic inflammation with the hypothesis that pancreaticcancer may arise from chronic inflammatory mechanisms.In a recent seminal study,Ethridge and colleagues in the laboratory have shown that COX-2 is a critical mediator ofpancreatic inflammation and that blocking COX-2, either by chemical inhibitors or geneticdeletion, attenuates pancreatic inflammation associated with acute pancreatitis.Investigators in our laboratory are also focused on a similar inflammatory mechanisms and theirrole in subsequent pancreatic cancer development.These studies may provide a therapeutictarget for the treatment of this devastating cancer.