Dosage-Dependent Hedgehog Signaling in Pancreatic Cancer

胰腺癌中剂量依赖性 Hedgehog 信号转导

• 批准号: 9762017
• 负责人: Benjamin Allen
• 金额: $ 36.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762017
• 关键词: Address; Adult; Affect; Alleles; Antibodies; Basal cell carcinoma; CDON gene; Cancer Etiology; Cell surface; Cessation of life; Clinical; Clinical Trials; Collaborations; Data; Disease; Dissection; Embryonic Development; Ensure; Erinaceidae; Fibroblasts; GLI Family Protein; GLI gene; Generations; Genetic; Genetic Transcription; Goals; Homeostasis; Impairment; Individual; Knowledge; Laboratories; Lesion; Ligands; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mus; Natural regeneration; Neoplasm Metastasis; Organ; Outcome; PTCH2 gene; Pancreas; Pathology; Pathway interactions; Pattern; Pharmacology; Play; Regulation; Research; Rhabdomyosarcoma; Role; Signal Transduction; Structure; Survival Rate; Testing; Tissues; Transgenes; Tumor Cell Line; Tumor-Derived; United States; Work; developmental disease; dosage; effective therapy; experimental study; hedgehog signal transduction; inhibitor/antagonist; insight; loss of function; medulloblastoma; mouse model; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutic intervention; pancreatic cancer model; pancreatic neoplasm; pancreatic tumorigenesis; paracrine; public health relevance; receptor; smoothened signaling pathway; tool; tumor; tumor growth; tumorigenesis

 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.

 描述（由应用提供）：刺猬（HH）信号在整个胚胎发育过程中起作用，以确保适当的组织模式和器官形成，而在成年人中，HH信号传导对于组织维持和稳态至关重要。异常的HH途径活性有助于多种发育疾病，并驱动了几种癌症的主动性和进展，包括基本细胞癌，横纹肌肉瘤和髓母细胞瘤。最近，在包括胰腺癌在内的多种其他癌症中实施了DEN调节的HH信号传导，其中肿瘤细胞衍生的HH配体以寄生虫方式向周围的微环境发出信号。特别是，胰腺癌的特征是广泛的HH响应性基质，可促进肿瘤生长。然而，对于HH信号在胰腺癌中起作用的机制知之甚少。我们建议通过对胰腺肿瘤生长中剂量依赖性HH信号的需求进行系统分析来解决我们知识中的这一关键差距。通过合作的努力，艾伦和帕斯卡·迪·马格里亚诺实验室确定，通过靶向HH共受体GAS1，BOC和CDON来改变HH信号传导的剂量，对胰腺肿瘤的生长进行了不同的调节。令人惊讶的是，与野生型胰腺成纤维细胞相比，当小鼠中肿瘤细胞时，缺乏这些共受体的胰腺成纤维细胞（GAS1和BOC）具有提高的肿瘤促进能力。相比之下，缺乏所有三个共受体的胰腺成纤维细胞无法促进胰腺肿瘤的生长。这些数据表明，HH信号的剂量会极大地影响胰腺肿瘤的生长。此外，这些发现具有重要的临床意义，并为胰腺癌中HH途径抑制剂的最新临床试验的负面结果提供了解释。那个提案中的主要问题是：不同水平的HH途径活动如何影响胰腺肿瘤的生长？该提案继续在艾伦和帕斯卡·迪·玛格丽亚诺实验室之间进行了独特的合作，该实验室结合了HH信号传导和胰腺癌的专业知识，以检验HH途径活性水平是胰腺肿瘤生长的必要调节剂的假设。这是该提案的目的是通过解剖剂量的1）HH配体，2）HH受体和3）下游HH信号转导组件来定义剂量依赖性HH信号传导在胰腺癌中的作用。 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.我们预计这些结果将定义HH信号在胰腺肿瘤生长中的作用，并将为成功靶向HH途径的新方法提供洞察力治疗胰腺癌和其他HH驱动的病理。

项目成果

Epithelial-Stromal Interactions in Pancreatic Cancer.

• DOI: 10.1146/annurev-physiol-020518-114515
• 发表时间: 2019-02
• 期刊: Annual review of physiology
• 影响因子: 18.2
• 作者: Yaqing Zhang;H. Crawford;M. Pasca di Magliano

Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop.

• DOI: 10.18632/oncotarget.6870
• 发表时间: 2016-02-09
• 期刊: Oncotarget
• 作者: Coffman LG;Choi YJ;McLean K;Allen BL;di Magliano MP;Buckanovich RJ
• 通讯作者: Buckanovich RJ

ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation.

• DOI: 10.1038/onc.2016.459
• 发表时间: 2017-06-01
• 期刊: Oncogene
• 影响因子: 8
• 作者: Dumartin L;Alrawashdeh W;Trabulo SM;Radon TP;Steiger K;Feakins RM;di Magliano MP;Heeschen C;Esposito I;Lemoine NR;Crnogorac-Jurcevic T
• 通讯作者: Crnogorac-Jurcevic T

Usp9x Promotes Survival in Human Pancreatic Cancer and Its Inhibition Suppresses Pancreatic Ductal Adenocarcinoma In Vivo Tumor Growth.

• DOI: 10.1016/j.neo.2017.11.007
• 发表时间: 2018-03
• 期刊: Neoplasia (New York, N.Y.)
• 作者: Pal A;Dziubinski M;Di Magliano MP;Simeone DM;Owens S;Thomas D;Peterson L;Potu H;Talpaz M;Donato NJ
• 通讯作者: Donato NJ