Dosage-Dependent Hedgehog Signaling in Pancreatic Cancer

 描述（由申请人提供）：Hedgehog（HH）信号传导在整个胚胎发育过程中发挥作用，以确保适当的组织模式和器官形成，而在成年人中，HH信号传导对组织维持和体内平衡至关重要。异常HH通路活性导致许多发育性疾病，并驱动几种癌症的发生和进展，包括基底细胞癌、横纹肌肉瘤和髓母细胞瘤。最近，去调节的HH信号传导已经涉及多种另外的癌症，包括胰腺癌，其中肿瘤细胞衍生的HH配体以旁分泌方式向周围微环境发出信号。特别是，胰腺癌的特征在于促进肿瘤生长的广泛的HH-响应性纤维化基质。然而，对HH信号在胰腺癌中的作用机制知之甚少。我们建议通过系统分析胰腺肿瘤生长中剂量依赖性HH信号传导的需求来解决我们知识中的这一关键空白。通过合作努力，艾伦和Pasca di Magliano实验室已经确定，通过靶向HH共受体GAS 1、BOC和CDON来改变HH信号传导的剂量可以差异性地调节胰腺肿瘤生长。令人惊讶的是，与野生型胰腺成纤维细胞相比，缺乏这些共受体中的两种（GAS 1和BOC）的胰腺成纤维细胞在与肿瘤细胞共注射到小鼠中时具有增加的肿瘤促进能力。相反，缺乏所有三种共受体的胰腺成纤维细胞不能促进胰腺肿瘤生长。这些数据表明HH信号传导的剂量显著影响胰腺肿瘤生长。此外，这些发现具有重要的临床意义，并为最近HH通路抑制剂在胰腺癌中的临床试验的阴性结果提供了解释。因此，该提案的中心问题是：不同水平的HH途径活性如何影响胰腺肿瘤生长？该提案延续了艾伦和Pasca di Magliano实验室之间的独特合作，结合了HH信号传导和胰腺癌的专业知识，以验证HH通路活性水平是胰腺肿瘤生长的重要调节因子的假设。因此，本提案的目的是通过分析胰腺肿瘤生长中对1）HH配体、2）HH受体和3）下游HH信号转导组分的需求，确定剂量依赖性HH信号传导在胰腺癌中的作用。这项工作的预期成果包括：1）全面分析胰腺肿瘤生长中对不同水平肿瘤源性HH配体的需求，2）阐明细胞表面HH受体和拮抗剂对胰腺癌间质促进的相对贡献，3）确定改变的下游HH途径活性对肿瘤生长和转移的影响。我们预计这些结果将定义HH信号传导在胰腺肿瘤生长中的作用，并将为成功靶向HH途径治疗胰腺癌和其他HH驱动的病理提供新方法的见解。

 DESCRIPTION (provided by applicant): Hedgehog (HH) signaling acts throughout embryonic development to ensure proper tissue patterning and organ formation, while in adults HH signaling is vital for tissue maintenance and homeostasis. Aberrant HH pathway activity contributes to numerous developmental diseases and drives the initiation and progression of several cancers, including basal cell carcinoma, rhabdomyosarcoma, and medulloblastoma. More recently, de-regulated HH signaling has been implicated in multiple additional cancers, including pancreatic cancer, where tumor cell-derived HH ligands signal in a paracrine manner to the surrounding microenvironment. In particular, pancreatic cancer is characterized by an extensive HH-responsive fibrotic stroma that promotes tumor growth. However, strikingly little is known about the mechanisms by which HH signaling acts in pancreatic cancer. We propose to address this critical gap in our knowledge through a systematic analysis of the requirement for dosage-dependent HH signaling in pancreatic tumor growth. Through a collaborative effort, the Allen and the Pasca di Magliano laboratories have determined that altering the dosage of HH signaling through targeting of the HH co-receptors GAS1, BOC and CDON differentially regulates pancreatic tumor growth. Surprisingly, pancreatic fibroblasts lacking two of these co-receptors (GAS1 and BOC) have increased tumor-promoting ability compared to wild-type pancreatic fibroblasts when co-injected with tumor cells in mice. In contrast, pancreatic fibroblasts lacking all three co-receptors are unable to promote pancreatic tumor growth. These data suggest that the dosage of HH signaling dramatically affects pancreatic tumor growth. Further, these findings have important clinical implications, and provide an explanation for the negative outcome of recent clinical trials of HH pathway inhibitors in pancreatic cancer. Thus, the central question in this proposal is: how do different levels of HH pathway activity affect pancreatic tumor growth? This proposal continues a unique collaboration between the Allen and Pasca di Magliano labs that combines expertise in HH signaling and pancreatic cancer to test the hypothesis that the level of HH pathway activity is an essential regulator of pancreatic tumor growth. Thus, the objective of this proposal is to define the role of dosage-dependent HH signaling in pancreatic cancer through the dissection of the requirement for 1) HH ligands, 2) HH receptors and 3) downstream HH signal transduction components in pancreatic tumor growth. The expected outcomes of this work include: 1) a comprehensive analysis of the requirement for different levels of tumor-derived HH ligands in pancreatic tumor growth, 2) the elucidation of the relative contributions of cell surface HH receptors and antagonists to stromal promotion of pancreatic cancer, and 3) a determination of the effects of altered downstream HH pathway activity on tumor growth and metastasis. We expect that these results will define the role of HH signaling in pancreatic tumor growth and will provide insight into novel approaches to successfully target the HH pathway in the treatment of pancreatic cancer and other HH-driven pathologies.