Role of TGFB Receptor Alterations in Pancreatic Cancer

描述（由申请人提供）：我们证实TbetaRII的表达缺失会导致具有完整SMAD通路的胰腺导管腺癌细胞（PDAC）群体对TGFbeta缺乏反应。TbetaRII表达的缺失通常是由涉及致癌ras信号、甲基化和HDAC的转录抑制引起的，而不是由RII基因突变引起的。有趣的是，我们发现tgf - β信号的缺失导致了PDAC中IGF-1R表达的失调。在PDAC中tgf - β反应性丧失的生物学后果包括通过调节bcl家族成员的生长控制放松和对凋亡的抵抗增加。我们建议测试以下假设：(1)致癌ras信号和表观遗传机制之间存在趋同，导致T？RII基因。为了解决这一假设，我们将确定ras信号、甲基化和HDAC调节TbetaRII表达的机制，并确定这些过程之间是否存在分子联系。为了实现这一点，我们建议(a)阐明T？受ras信号、甲基化和HDAC影响的RII基因和(b)确定ras、甲基化和HDAC之间是否存在导致T？RII基因。(2) tgf - β信号的缺失有利于生长因子的独立性和对细胞凋亡的抵抗，这在一定程度上是通过促进lGF-1R表达的失调来实现的。为了解决这一假设，我们将确定tgf - β介导的PDAC中IGF-1R信号抑制的生物学后果。为了实现这一目标，我们提出(a)确定自分泌tgf - β信号的丢失是否代表PDAC中IGF-1R表达失调的共同机制，(b)确定tgf - β信号是否通过c- myc调节IGF-IR表达，以及(c)确定IGF-IR和tgf - β途径在细胞周期调节和致瘤性中的相互作用的生物学意义。开发克服TbetaRII转录抑制的策略可能为治疗和提高PDAC对化疗或放疗的敏感性提供新的途径。

DESCRIPTION (provided by applicant): 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.