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

描述(申请人提供)：在转化生长因子时-？(转化生长因子？)具有双重抑癌/促癌作用的肿瘤发生，还有其他的转化生长因子作用吗？超家族配体，包括骨形态发生蛋白(BMPs)，刚刚被定义。转化生长因子-？超家族配体利用一种信号辅助受体，即III型转化生长因子？受体(T？RIII)，通过I型和II型转化生长因子受体介导和调节配体结合和信号传导。超家族受体。T？RIII还经历胞外结构域的脱落，产生一种天然的可溶性T？RIII(ST？RIII)，我们在人血浆中检测到这种形式。我们最近证实，T？RIII也是BMP辅助受体，在某些BMP介导的生物学中是必需的，并且T？RIII和BMP在胰腺癌的EMT和进展中起作用。为了探讨T？RIII在人胰腺癌中的作用机制，提出如下假说：BMP在胰腺癌进展中具有二分性作用，部分是通过T？RIII表达的丢失和ALK-6信号的减少而丧失自分泌BMP的反应性，部分是通过丢失ST？RIII的表达促进肿瘤的启动和BMP水平的升高，然后通过EMT介导的细胞运动和侵袭力的增加来促进肿瘤的进展。这一假设将通过四个具体目标来解决。特异性Aim1：T？RIII调节转化生长因子-β的相对生物活性的机制通过定义介导T？RIII配体与骨形态发生蛋白结合的结构决定因素，确定转化生长因子-β受体的相对配体结合层级，探索胰腺癌中的超家族配体。T？RIII和ST？RIII的超家族配体，确定ST？RIII是否作为骨形态发生蛋白信号的拮抗剂，以及T？RIII和ST？RIII的相对表达是否调节转化生长因子？胰腺癌细胞中的超家族配体。特异的AIM2：T？RIII选择性地通过ALK-6增加BMP信号的机制将通过确定T？RIII是否选择性地介导ALK-6与？-arrestin2的相互作用选择性地介导ALK-6的内化，以及T？RIII介导的ALK-3/ALK-6内化是否是BMP信号和BMP介导的生物学所必需的。特异性Aim3：细胞表面T？RIII、循环ST？RIII和循环活性转化生长因子？将在小鼠模型和人类样本中建立超家族成员，以确定这些水平在胰腺癌进展过程中是否受到协调调控。目的：建立T？RIII和/或ST？RIII在小鼠胰腺癌发生和发展模型中的表达上调或下调效应，以明确T？RIII和/或ST？RIII在胰腺癌发生和发展中是否具有相反的作用。这些研究将确定T？RIII协调转化生长因子-？的机制。超家族信号调节胰腺癌的发生和发展，确定T？RIII胞外结构域缺失在胰腺癌背景下的生物学意义，并帮助靶向这些途径预防和治疗人类癌症。 公共卫生相关性：我们已经证明了一种细胞表面转化生长因子受体-？(转化生长因子？)超家族配体，III型转化生长因子-？受体(T？RIII)能够通过降低癌细胞迁移、侵袭和扩散到远处的能力来抑制多种人类癌症的进展，包括乳腺癌、肺癌、卵巢癌、胰腺癌和前列腺癌。我们最近还证实，T？RIII能够结合和调节另一个亚家族的信号转导。超家族配体，骨形态发生蛋白(BMPs)，以及T？RIII和BMPs在胰腺癌进展中都起作用。因此，我们将研究T？RIII在胰腺癌中调节转化生长因子-2超家族配体功能的机制，这些研究具有重要的意义，并与公众健康相关，因为这些机制见解将在人类胰腺癌的背景下定义T？RIII的生物学功能，增加对转化生长因子-2的作用的理解。超家族信号转导和T？RIII在调节肿瘤生物学中的作用，并帮助靶向转化生长因子？治疗癌症和其他疾病的超家族信号通路中，转化生长因子？超家族信号通路起着非常重要的作用。

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.