We established that loss of expression of TbetaRII causes a lack of response to TGFbeta in a population of pancreatic ductal adenocarcinoma cells (PDAC) that otherwise has an intact SMAD pathway. The loss of TbetaRII expression was most often caused by transcriptional repression involving oncogenic ras signaling, methylation, and HDAC and not by a mutation of the RII gene. Interestingly, we found that loss of TGFbeta signaling contributed to the deregulation of IGF-1R expression found in PDAC. The biologic consequences of loss of TGFbeta responsiveness in PDAC include a relaxation of growth controls and an increase in resistance to apoptosis through modulation of bcl-family members. We propose to test the hypotheses that: (1) there is a convergence between oncogenic ras signaling and epigenetic mechanisms leading to a transcriptional repression of the T?RII gene. To address this hypothesis we will determine the mechanism(s) by which ras signaling, methylation and HDAC regulate TbetaRII expression and determine whether there is a molecular linkage among these processes. To accomplish this we propose to (a) elucidate the transcriptional components of the T?RII gene affected by ras signaling, methylation and HDAC and (b) determine whether there is a molecular linkage among ras, methylation and HDAC in causing transcriptional repression of the T?RII gene. (2) the loss of TGFbeta signaling favors growth factor independence and resistance to apoptosis, in part, by promoting deregulation of lGF-1R expression. To address this hypothesis we will determine the biologic consequence of TGFbeta-mediated suppression of IGF-1R signaling in PDAC. To accomplish this we propose to (a) determine whether loss of autocrine TGFbeta signaling represents a common mechanism for deregulation of IGF-1R expression in PDAC, (b) determine whether TGFbeta signaling regulates IGF-IR expression through c-Myc and (c) determine the biologic significance of the interaction of IGF-IR and TGFbeta pathways in cell cycle regulation and tumorigenicity. Developing strategies to overcome transcriptional repression of TbetaRII may provide a new approach for therapy and for increasing sensitivity of PDAC to chemotherapy or radiation.
Showing the most recent 10 out of 15 publications
