Molecular Basis of Epithelial Skin Cancer

上皮性皮肤癌的分子基础

• 批准号: 8620610
• 负责人: ANDRZEJ A. DLUGOSZ
• 金额: $ 30.17万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8620610
• 关键词: Basal Cell; Basal Cell Cancer; Basal cell carcinoma; Benign; Biological; Cells; Clinic; Development; Embryo; Epithelial; Erinaceidae; Funding; Gastric Adenocarcinoma; Gene Deletion; Genes; Genetic; Goals; Grant; Growth; Hair; Hair follicle structure; Hamartoma; Human; Lead; Ligands; Location; Maintenance; Malignant Neoplasms; Malignant Peripheral Nerve Sheath Tumor; Mediating; Molecular; Mus; Nature; Neoplastic Cell Transformation; Oncogenic; Pathogenesis; Pathway interactions; Phenotype; Physiological; Play; Population; Process; Proliferating; Resistance; Rest; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Neoplasms; Staging; Stem cells; Stomach; Testing; Work; Wound Healing; base; beta catenin; cancer type; cell type; chromatin remodeling; inhibitor/antagonist; insight; keratinocyte; medulloblastoma; mouse model; neoplastic cell; novel strategies; prevent; progenitor; public health relevance; receptor; regenerative; response; smoothened signaling pathway; stem cell niche; tissue regeneration; tumor; tumor initiation; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Cancer development is associated with reactivation of several 'embryonic' signaling pathways, including the Hedgehog pathway, and our long-term goal in this grant has been to gain insight into how deregulated Hedgehog signaling contributes to tumor development. Our previous studies have been focused on basal cell carcinoma, a common skin tumor, and several other cancers associated with deregulated Hedgehog signaling. Activation of the Hedgehog (Hh)/Gli pathway in skin leads to formation of benign tumors called follicular hamartomas, basal cell carcinomas, or other follicular tumors. Both follicular hamartomas and basal cell carcinomas express multiple Wnt ligands, leading in both cases to activation of the canonical Wnt/beta-catenin pathway. While it has been shown that follicular hamartomas are strictly dependent on canonical Wnt/beta-catenin signaling for their formation, it is not known whether Wnt signaling plays a similarly important role in basal cell carcinomas and other malignant tumors driven by the Hh/Gli pathway. Although basal cell carcinoma tumor progenitors reside within the epithelial stem cell niche of the hair follicle, called the bulge, mobilization to form a transit amplifying cell population (a Wnt-mediated process) is required for tumorigenesis, underscoring the importance of a regenerative response in tumor development. We hypothesize that the phenotype of epithelial tumors arising in skin is determined by the nature of the oncogenic alteration(s), crosstalk with other signaling pathways, the location of potential tumor progenitors within their lineage, and tumor-promoting effects associated with tissue regeneration, either physiological (e.g., cyclical hair follicle growth) or pathological (wound-healing). We propose to begin exploring these relationships using state-of-the-art mouse models and a pharmacological inhibitor of Wnt signaling. In Aim 1 of this proposal, we will test the importance of canonical Wnt/beta-catenin signaling in the pathogenesis of basal cell carcinoma using genetic and pharmacological approaches. In Aim 2, we will determine the contribution of specific hair follicle cell compartments to Hedgehog/Gli-driven tumorigenesis, and assess the role of tissue regeneration in this process. In Aim 3, we will investigate the contribution of differentiated cell types to Hedgehog/Gli- and Ras-driven tumorigenesis in skin. These studies will yield new insights into the mechanisms underlying skin tumorigenesis, and are likely to lead to new approaches to the treatment of malignancies in which functionally relevant interactions exist between the Hh/Gli and Wnt pathways.

描述(由申请者提供)：癌症的发展与几个“胚胎”信号通路的重新激活有关，包括Hedgehog通路，我们在这笔赠款中的长期目标是深入了解解除管制的Hedgehog信号如何促进肿瘤的发展。我们之前的研究集中在基底细胞癌，一种常见的皮肤肿瘤，以及其他几种与去调控的Hedgehog信号相关的癌症。皮肤中Hedgehog(HH)/Gli途径的激活会导致良性肿瘤的形成，称为滤泡性错构瘤、基底细胞癌或其他滤泡性肿瘤。滤泡性错构瘤和基底细胞癌都表达多个Wnt配体，导致规范的Wnt/β-catenin途径的激活。虽然已有研究表明滤泡性错构瘤的形成严格依赖于典型的Wnt/β-catenin信号，但Wnt信号在基底细胞癌和其他由HH/Gli途径驱动的恶性肿瘤中是否起着同样重要的作用尚不清楚。尽管基底细胞癌肿瘤前体细胞驻留在毛囊的上皮干细胞利基内，称为突起，但肿瘤发生需要动员以形成过渡放大细胞群(Wnt介导的过程)，这突显了再生反应在肿瘤发展中的重要性。我们假设，皮肤上皮肿瘤的表型取决于致癌改变的性质(S)、与其他信号通路的交叉性、潜在肿瘤前体细胞在其谱系中的位置以及与组织再生相关的促肿瘤效应，无论是生理性的(如毛囊周期性生长)还是病理的(伤口愈合)。我们建议开始使用最先进的小鼠模型和Wnt信号的药理抑制剂来探索这些关系。在这项提案的目标1中，我们将使用遗传学和药理学方法测试规范的Wnt/β-catenin信号在基底细胞癌发病机制中的重要性。在目标2中，我们将确定特定毛囊细胞室在Hedgehog/Gli驱动的肿瘤发生中的作用，并评估组织再生在这一过程中的作用。在目标3中，我们将研究分化的细胞类型在Hedgehog/Gli和RAS驱动的皮肤肿瘤发生中的作用。这些研究将对皮肤肿瘤发生的机制产生新的见解，并可能导致治疗恶性肿瘤的新方法，其中HH/Gli和Wnt通路之间存在功能相关的相互作用。

项目成果

Inflammation and Gli2 suppress gastrin gene expression in a murine model of antral hyperplasia.

• DOI: 10.1371/journal.pone.0048039
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Saqui-Salces M;Covés-Datson E;Veniaminova NA;Waghray M;Syu LJ;Dlugosz AA;Merchant JL
• 通讯作者: Merchant JL

Montagna Symposium 2011: 60th Anniversary--Advances in Science and Medicine Catalyzed by Pioneering Skin Research.

2011 年蒙塔尼亚研讨会：60 周年——开创性皮肤研究推动科学和医学的进步。

• DOI: 10.1038/jid.2011.480
• 发表时间: 2012
• 期刊: The Journal of investigative dermatology
• 作者: Yuspa,StuartH;Kraemer,KennethH;Dlugosz,AndrzejA;Roop,DennisR;Kulesz-Martin,Molly;Bickenbach,JackieR
• 通讯作者: Bickenbach,JackieR

Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia.

在慢性淋巴细胞性白血病的启动和维持中，刺猬/GLI和PI3K信号传导。

• DOI: 10.1038/onc.2014.450
• 发表时间: 2015-10-16
• 期刊: Oncogene
• 影响因子: 8

Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma.

• DOI: 10.1016/j.ccell.2015.02.001
• 发表时间: 2015-03-09
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Sharpe HJ;Pau G;Dijkgraaf GJ;Basset-Seguin N;Modrusan Z;Januario T;Tsui V;Durham AB;Dlugosz AA;Haverty PM;Bourgon R;Tang JY;Sarin KY;Dirix L;Fisher DC;Rudin CM;Sofen H;Migden MR;Yauch RL;de Sauvage FJ
• 通讯作者: de Sauvage FJ

Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells.

• DOI: 10.1002/emmm.201100201
• 发表时间: 2012-03
• 期刊: EMBO MOLECULAR MEDICINE
• 影响因子: 11.1
• 作者: Eberl, Markus;Klingler, Stefan;Mangelberger, Doris;Loipetzberger, Andrea;Damhofer, Helene;Zoidl, Kerstin;Schnidar, Harald;Hache, Hendrik;Bauer, Hans-Christian;Solca, Flavio;Hauser-Kronberger, Cornelia;Ermilov, Alexandre N.;Verhaegen, Monique E.;Bichakjian, Christopher K.;Dlugosz, Andrzej A.;Nietfeld, Wilfried;Sibilia, Maria;Lehrach, Hans;Wierling, Christoph;Aberger, Fritz
• 通讯作者: Aberger, Fritz