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

描述(申请人提供)：肝硬变和慢性胰腺炎分别是肝细胞癌和胰腺导管腺癌的公认危险因素。间质纤维化积极地促进了肿瘤的发生、转移和对治疗的抵抗。纤维化间质的形成是通过激活静止的星状细胞进入肌成纤维细胞状态，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-？(转化生长因子-？？)在肝硬变、胰腺炎和癌变过程中，信号在促进这种病理激活中起着核心作用。III型转化生长因子？受体(T？RIII)介导转化生长因子-β？通过调节配体结合和与细胞质蛋白的相互作用来传递信号--阻滞素2、GIPC和E3泛素连接酶TRAF6。T？RIII抑制多种上皮源性癌症的迁移、侵袭和转移，在肿瘤进展过程中经常丢失T？RIII的表达。转化生长因子-？通过TRAF6诱导p38MAPK信号转导，我们的初步研究表明，转化生长因子β-p38MAPK信号转导通路在促进肌成纤维细胞活化中起重要作用。然而，T？RIII-TRAF6相互作用在转化生长因子β诱导的p38MAPK信号转导中的作用尚不清楚。根据初步研究表明T？RIII在肌成纤维细胞激活过程中表达缺失，提出如下假说：T？RIII通过TRAF6介导的抑制转化生长因子β诱导的p38MAPK信号通路抑制星状细胞激活，从而抑制肿瘤进展，在PDAC和肝细胞癌的纤维间质星状细胞激活过程中T？RIII表达缺失，从而促进肿瘤进展。这一假设将通过三个具体目标来解决。具体目的1：研究T？RIII在星状细胞体外活化和VIV毒素诱导的纤维化模型中的作用，以确定T？RIII是否调节转化生长因子β诱导的肌成纤维细胞激活和ECM的分泌。具体目标2：T？RIII-TRAF6相互作用在转化生长因子β诱导的p38MAPK信号转导中的作用以及该通路在星状细胞激活和肿瘤进展中的作用。具体目标3：确定T？RIII在星状细胞中的表达对邻近癌细胞生物学的贡献，以确定在星状细胞激活过程中T？RIII的表达缺失是否有助于肿瘤的生长和转移。这些研究将确定T？RIII在肌成纤维细胞激活和ECM分泌中的作用，促进针对纤维间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.