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。纤维化间质积极促进致癌、转移和治疗抵抗。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-β（TGF-β）信号传导在肝硬化、胰腺炎和癌变过程中促进这种病理激活中起着核心作用。III型TGF-β受体（TβRIII）通过调节配体结合以及与细胞质蛋白β-抑制蛋白2、GIPC和E3泛素连接酶TRAF 6的相互作用介导TGF-β信号传导。TβRIII抑制多种上皮来源的癌症的迁移、侵袭和转移，在癌症进展期间TβRIII表达经常丢失。TGF-β通过TRAF 6诱导p38 MAPK信号通路，我们的初步研究表明TGF-β-p38 MAPK信号通路在促进肌成纤维细胞活化中起重要作用。然而，Tβ RIII-TRAF 6相互作用在TGFβ诱导的p38 MAPK信号转导中的作用仍有待阐明。基于初步研究显示TβRIII表达在肌成纤维细胞活化期间丢失，提出以下假设：TβRIII通过TRAF 6介导的TGFβ诱导的p38 MAPK信号转导抑制星状细胞活化，从而抑制癌症进展，PDAC和HCC纤维化基质中星状细胞活化期间TβRIII表达的丢失有助于癌症进展。这一假设将通过三个具体目标来解决。具体目标1：将在体外星状细胞活化和毒素诱导的纤维化体内模型中检查TβRIII的作用，以确定TβRIII是否调节TGFβ诱导的肌成纤维细胞活化和ECM分泌。具体目标二：将确定Tβ RIII-TRAF 6相互作用对TGFβ诱导的p38 MAPK信号传导的贡献以及该途径对星状细胞活化和癌症进展的影响。具体目标3：将确定星状细胞中TβRIII表达对邻近癌细胞生物学的贡献，以确定星状细胞活化期间TβRIII表达的缺失是否有助于肿瘤生长和转移。这些研究将确定TβRIII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-β (TGF-β) signaling plays a central role in promoting this pathological activation during cirrhosis, pancreatitis, and carcinogenesis. The type III TGF-β receptor (TβRIII) mediates TGF-β signaling through regulation of ligand binding and interaction with the cytoplasmic proteins β-arrestin2, GIPC, and the E3 ubiquitin ligase TRAF6. TβRIII inhibits migration, invasion, and metastasis in multiple epithelial-derived cancers, with TβRIII expression frequently lost during cancer progression. TGF-β induces p38 MAPK signaling via TRAF6, and our preliminary studies indicate TGFβ-p38 MAPK signaling plays an important role in promoting myofibroblast activation. However, the role of the TβRIII-TRAF6 interaction in TGFβ-induced p38 MAPK signaling remains to be elucidated. Based on preliminary studies showing TβRIII expression is lost during myofibroblast activation, the following hypothesis is proposed: TβRIII homeostatically inhibits stellate cell activation through TRAF6-mediated inhibition of TGFβ-induced p38 MAPK signaling, resulting in inhibition of cancer progression, with loss of TβRIII 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 TβRIII will be examined in in vitro stellate cell activation and in viv models of toxin-induced fibrosis to determine whether TβRIII regulates TGFβ-induced myofibroblast activation and ECM secretion. Specific Aim 2: The contribution of the TβRIII-TRAF6 interaction to TGFβ-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 TβRIII expression in stellate cells to the biology of the neighboring cancer cells will be established to determine whether loss of TβRIII expression during stellate cell activation contributes to tumor growth and metastasis. These studies will determine the role of TβRIII in myofibroblast activation and ECM secretion, facilitating targeting of the fibrotic stroma for the treatment of these deadly cancers.