This interactive and collaborative research program seeks to determine the relationship and regulation of "new" genes identified in tumor cells to the neoplastic process and how these may differ from their normal physiological roles. Two genes (with multiple names reflecting their study now in several laboratories) identified and under intense scrutiny in our lab, TuAg.1/Tage4 and TA1/E16/LAT-1, were discovered in the rat liver system but have been found to have close relatives expressed in human cancer. Long term objectives of this research are to define molecular mechanisms of neoplasia using hepatic model systems and explore their relation to normal injury-response and developmental pathways. In study of these genes, our group is committed to furthering basic understanding of disease processes as well as seeking clinical applications to benefit patients

TA1/E16/LAT-1 is a hydrophobic integral membrane protein recently found to be the light chain of the CD98 heterodimer, a molecule associated with amino acid transport, cell activation, and integrin activation. The light chain is highly conserved and homologs have been found in distant organisms including parasites and frogs. The rat and human molecules are 95% identical. Our studies demonstrate that TA1/E16/LAT-1 expression is upregulated in rat and human primary cancers and cell lines while CD98 heavy chain expression appears to be constitutive. TA1 expression is altered in hepatic cells in response to the amino acid availability. The mechanism responsible for this response is currently under investigation. Studies in progress are examining our key hypothesis that the CD98 complex, particularly TA1/E16/LAT-1 light chain provides an adaptive advantage to tumor cells, supporting higher metabolic demands, particularly under conditions of nutrient stress.

TuAg.1 is a cell surface glycoprotein originally discovered on the basis of its differential expression in rat hepatocarcinogenesis. It is a member of the immunoglobulin (Ig) superfamily, closely related to a gene cloned from rat colon and mammary carcinomas, and has an undefined human homolog with apparent expression in gastrointestinal carcinomas. It is expressed in fetal liver and liver injury as well. We hypothesize that like other Ig family members, TuAg.1 plays a recognition and signaling function and that its expression conveys an adaptive advantage in liver oncoinjury. TuAg.1 expression may result from, or alternatively, result in, alterations in cellular interactions or polarity that are common between carcinogenesis, development and injury response. In this regard, TuAg.1 may be a relay for environmental cues. Strategies to define the molecules with which it interacts, cancer phenotypes to which it contributes and cellular processes in which it acts are underway.