Function of TbRIII as a BMP Co-receptor in Human Cancer

描述（由申请人提供）：转化生长因子-？（TGF-?）在肿瘤发生中具有双重抑瘤/促瘤作用，其他TGF-？超家族配体，包括骨形态发生蛋白（BMPs），刚刚被定义。TGF - ?超家族配体利用信号辅助受体III型TGF-？受体(T ?iii)，通过I型和II型TGF-?介导和调节配体结合和信号传导。总科受体。T ?iii也经历胞外结构域脱落以产生天然可溶性的T？RIII(圣?iii)，我们已在人血浆中检测到。我们最近确定了T？RIII也作为BMP共受体发挥作用，是一些BMP介导的生物学所必需的。iii和BMP在胰腺癌EMT和进展中起作用。探讨T？RIII在人类胰腺癌中的功能提出了以下假设：BMP对胰腺癌进展具有双重作用，失去自分泌BMP反应性，部分原因是由于T？RIII的表达和ALK-6信号的减少，促进了癌症的发生和BMP水平的升高，部分是由于sT？RIII的表达，然后通过emt介导的细胞运动性和侵袭性的增加促进癌症的进展。这一假设将通过四个具体目标来解决。具体目标1:T？iii调控TGF-?的相对生物活性胰腺癌中的超家族配体将通过定义介导T？RIII配体结合BMP，确定TGF-？超家族配体到T？iii和sT？三、确定sT？RIII作为BMP信号的拮抗剂，以及T？iii和sT？iii调节TGF-?的细胞效应胰腺癌细胞中的超家族配体。具体目标2:T？RIII通过ALK-6选择性地增加BMP信号将通过定义T？RIII选择性地介导ALK-6与？-arrestin2选择性介导ALK-6的内化，并确定T？RIII介导的ALK-3/ALK-6内化是BMP信号传导和BMP介导的生物学所必需的。特异性目标：细胞表面T？三、循环sT？iii和循环活性TGF-？将在小鼠模型和人类标本中建立超家族成员，以确定这些水平是否在胰腺癌进展过程中得到协调调节。特异性Aim4：增加或减少T？iii及/或sT？RIII在小鼠胰腺癌起始和进展模型中的表达将被建立，以确定T？iii及/或sT？iii对胰腺癌的发生和发展有相反的作用。这些研究将确定T？iii调控TGF-？超家族信号调节胰腺癌的发生和发展，定义T？iii外结构域脱落在胰腺癌的背景下，并有助于针对这些途径预防和治疗人类癌症。

DESCRIPTION (provided by applicant): While transforming growth factor-? (TGF-?) has a dual tumor suppressor/tumor promoter role in tumorigenesis, the role of other TGF-? superfamily ligands, including the bone morphogenetic proteins (BMPs), is just being defined. TGF-? superfamily ligands utilize a signaling coreceptor, the type III TGF-? receptor (T?RIII), to mediate and regulate ligand binding and signaling through the type I and type II TGF-? superfamily receptors. T?RIII also undergoes ectodomain shedding to produce a natural soluble form of T?RIII (sT?RIII), which we have detected in human plasma. We have recently established that T?RIII also functions as a BMP co-receptor and is required for some BMP-mediated biology, and that T?RIII and BMP have roles in pancreatic cancer EMT and progression. To investigate the mechanism of T?RIII function in human pancreatic cancer the following hypothesis is proposed: BMPs have dichotomous effects on pancreatic cancer progression, with loss of autocrine BMP responsiveness, in part through loss of T?RIII expression and decreased ALK-6 signaling, facilitating cancer initiation and elevated BMP levels, in part through loss of sT?RIII expression, then promoting cancer progression through EMT-mediated increases in cellular motility and invasiveness. This hypothesis will be addressed by four Specific Aims. Specific Aim1: The mechanism by which T?RIII orchestrates the relative bioactivity of TGF-? superfamily ligands in pancreatic cancer will be explored by defining the structural determinants mediating T?RIII ligand binding to BMP, determining the relative ligand binding hierarchy of TGF-? superfamily ligands to T?RIII and sT?RIII, establishing whether sT?RIII serves as an antagonist of BMP signaling and whether the relative expression of T?RIII and sT?RIII regulate the cellular effects of TGF-? superfamily ligands in pancreatic cancer cells. Specific Aim2: The mechanism by which T?RIII selectively increases BMP signaling through ALK-6 will be established by defining whether T?RIII selectively mediates the interaction of ALK-6 with ?-arrestin2 to selectively mediate the internalization of ALK-6 and establishing whether T?RIII mediated ALK-3/ALK-6 internalization is necessary for BMP signaling and BMP-mediated biology. Specific Aim3: The levels of cell surface T?RIII, circulating sT?RIII and circulating active TGF-? superfamily members will be established in murine models and human specimens to establish whether these levels are coordinately regulated during pancreatic cancer progression. Specific Aim4: The effect of increasing or decreasing T?RIII and/or sT?RIII expression in murine pancreatic cancer models of initiation and progression will be established to define whether T?RIII and/or sT?RIII have opposing effects on pancreatic cancer initiation and progression. These studies will define the mechanism by which T?RIII orchestrates TGF-? superfamily signaling to regulate the initiation and progression of pancreatic cancer, define the biological implications of T?RIII ectodomain shedding in the context of pancreatic cancer and aid in targeting these pathways for the prevention and treatment of human cancers. PUBLIC HEALTH RELEVANCE: We have demonstrated that a cell surface receptor for transforming growth factor-? (TGF-?) superfamily ligands, the type III TGF-? receptor (T?RIII), is able to suppress cancer progression in a broad spectrum of human cancers, including cancers of the breast, lung, ovary, pancreas and prostate, by decreasing the ability of the cancer cells to migrate, invade and spread to distant sites. We have also recently established that T?RIII is able to bind and regulate signaling of another subfamily of TGF-? superfamily ligands, the bone morphogenetic proteins (BMPs), and that both T?RIII and BMPs have a role in pancreatic cancer progression. Thus, these studies where we will investigate mechanisms by which T?RIII regulates TGF-?2 superfamily ligand function in pancreatic cancer are important to perform and relevant to public health as these mechanistic insights will define the biological functions of T?RIII in the context of human pancreatic cancers, increase understanding of the role of TGF-? superfamily signaling and of T?RIII in regulating tumor biology, and aid in targeting TGF-? superfamily signaling pathways for the treatment of cancers and other diseases in which TGF-? superfamily signaling pathways have a prominent role.