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

描述（由申请人提供）：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）的危险因素。纤维化间质积极促进癌变、转移和对治疗的抵抗。纤维化基质的形成是通过将静止的星状细胞激活为肌成纤维细胞状态而发生的，其特征是过度分泌细胞外基质（ECM）成分和生长因子。转化生长因子-？（TGF-??）信号在肝硬化、胰腺炎和癌变过程中促进这种病理激活起核心作用。III型TGF-？受体(T ?iii)介导TGF-？通过调节配体结合和与细胞质蛋白相互作用的信号传导？-arrestin2， GIPC和E3泛素连接酶TRAF6。T ?iii抑制多种上皮源性癌症的迁移、侵袭和转移。在癌症进展过程中，RIII的表达经常丢失。TGF - ?通过TRAF6诱导p38 MAPK信号，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？iii - traf6在TGF？诱导的p38 MAPK信号仍有待阐明。初步研究表明，T？RIII表达在肌成纤维细胞活化过程中丢失，提出以下假设：iii通过traf6介导的TGF?抑制星状细胞活化-诱导的p38 MAPK信号，导致抑制癌症进展，失去T？在PDAC和HCC纤维化基质中星状细胞活化过程中，RIII的表达促进了癌症的进展。这一假设将通过三个具体目标来解决。具体目标1:T？RIII将在体外星状细胞活化和毒素诱导纤维化的体内模型中进行检查，以确定T？RIII调节TGF？诱导的肌成纤维细胞活化和ECM分泌。具体目标2:T？iii - traf6与TGF？-诱导的p38 MAPK信号通路以及该通路对星状细胞激活和癌症进展的影响将被建立。具体目标3:T？RIII在星状细胞中的表达将对邻近癌细胞的生物学特性进行建立，以确定是否丢失T？星状细胞激活过程中RIII的表达有助于肿瘤的生长和转移。这些研究将确定T？RIII参与肌成纤维细胞活化和ECM分泌，促进靶向纤维化基质治疗这些致命癌症。

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.