The Role of Type III TGF-beta Receptor in the Fibrotic Tumor Stroma

描述（由申请方提供）：肝硬化和慢性胰腺炎分别是肝细胞癌（HCC）和胰腺导管腺癌（PDAC）的公认风险因素。纤维化间质积极地促进癌发生、转移和对治疗的抵抗。纤维化基质的形成通过将驻留的静止星状细胞活化为肌成纤维细胞状态而发生，其特征在于细胞外基质（ECM）组分和生长因子的过度分泌。转化生长因子-？(TGF-??)信号传导在肝硬化、胰腺炎和癌发生过程中促进这种病理活化中起着中心作用。III型TGF-？受体（T？RIII）介导TGF-？通过调节配体结合和与细胞质蛋白质相互作用的信号传导？抑制蛋白2、GIPC和E3泛素连接酶TRAF6。T？RIII抑制多种上皮来源的癌症的迁移，侵袭和转移，与T？RIII表达在癌症进展过程中经常丢失。TGF-β？通过TRAF6诱导p38 MAPK信号传导，我们的初步研究表明TGF？p38 MAPK信号在促进肌成纤维细胞活化中起重要作用。然而，T的作用？TGF？中的RIII-TRAF6相互作用-诱导的p38 MAPK信号转导仍有待阐明。根据初步研究显示T？RIII表达在肌成纤维细胞活化过程中丢失，提出以下假设：T？RIII通过TRAF6介导的TGF β-抑制作用稳态抑制星状细胞活化。诱导p38 MAPK信号转导，导致抑制癌症进展，与损失的T？PDAC和HCC纤维化间质中星状细胞活化期间RIII表达促进癌症进展这一假设将通过三个具体目标来解决。具体目标1：T的作用？RIII将在体外星状细胞活化和体内毒素诱导的纤维化模型中进行检查，以确定T？RIII调节TGF？-诱导肌成纤维细胞活化和ECM分泌。具体目标2：T？RIII-TRAF6与TGF？的相互作用-诱导的p38 MAPK信号传导以及该途径对星状细胞活化和癌症进展的作用将被确定。具体目标3：T？RIII在星状细胞中的表达对邻近癌细胞的生物学特性的影响将被建立，以确定T细胞是否丢失？星状细胞活化过程中RIII的表达有助于肿瘤的生长和转移。这些研究将确定T？RIII在肌成纤维细胞活化和ECM分泌中的作用，促进靶向纤维化基质以治疗这些致命的癌症。

DESCRIPTION (provided by applicant): Cirrhosis and chronic pancreatitis are well-established risk factors for hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) respectively. The fibrotic stroma actively contributes to carcinogenesis, metastasis, and resistance to therapy. Formation of the fibrotic stroma occurs through activation of resident quiescent stellate cells to a myofibroblast state, which is characterized by excessive secretion of extracellular matrix (ECM) components and growth factors. Transforming growth factor-? (TGF-??) signaling plays a central role in promoting this pathological activation during cirrhosis, pancreatitis, and carcinogenesis. The type III TGF-? receptor (T?RIII) mediates TGF-? signaling through regulation of ligand binding and interaction with the cytoplasmic proteins ?-arrestin2, GIPC, and the E3 ubiquitin ligase TRAF6. T?RIII inhibits migration, invasion, and metastasis in multiple epithelial-derived cancers, with T?RIII expression frequently lost during cancer progression. TGF-? induces p38 MAPK signaling via TRAF6, and our preliminary studies indicate TGF?-p38 MAPK signaling plays an important role in promoting myofibroblast activation. However, the role of the T?RIII-TRAF6 interaction in TGF?-induced p38 MAPK signaling remains to be elucidated. Based on preliminary studies showing T?RIII expression is lost during myofibroblast activation, the following hypothesis is proposed: T?RIII homeostatically inhibits stellate cell activation through TRAF6-mediated inhibition of TGF?-induced p38 MAPK signaling, resulting in inhibition of cancer progression, with loss of T?RIII expression during stellate cell activation in the fibrotic stroma of PDAC and HCC contributing to cancer progression. This hypothesis will be addressed by 3 specific aims. Specific Aim 1: The role of T?RIII will be examined in in vitro stellate cell activation and in viv models of toxin-induced fibrosis to determine whether T?RIII regulates TGF?-induced myofibroblast activation and ECM secretion. Specific Aim 2: The contribution of the T?RIII-TRAF6 interaction to TGF?-induced p38 MAPK signaling and the effect of this pathway on stellate cell activation and cancer progression will be established. Specific Aim 3: The contribution of T?RIII expression in stellate cells to the biology of the neighboring cancer cells will be established to determine whether loss of T?RIII expression during stellate cell activation contributes to tumor growth and metastasis. These studies will determine the role of T?RIII in myofibroblast activation and ECM secretion, facilitating targeting of the fibrotic stroma for the treatment of these deadly cancers.