Molecular Characterization of Autophagy in Salivary Gland Tumors

唾液腺肿瘤自噬的分子特征

基本信息

  • 批准号:
    8681423
  • 负责人:
  • 金额:
    $ 23.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-07-01 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to elucidate how autophagy regulates the onset and progression of salivary gland tumors, and how the pathway interacts with oncogenic signaling pathways during tumorigenesis. Salivary gland tumors are both rare and highly varied. Because of their rarity, previous investigation of salivary cancer is limited an as yet, there are no useful mouse models of salivary gland cancer available that resemble the pathophysiology of human salivary cancers. Consequently, therapeutic options for salivary tumors are limited, personalized treatment is virtually non-existent and there is a glaring lack of pre-clinical and clinical validation. Autophagy is a catabolic process that uses the cell's lysosomal system to degrade its own components including cytoplasmic organelles and proteins. In the last decade, it has been established that autophagy plays important and complicated roles in the onset and progression of tumors via multiple mechanisms. It is therefore a promising therapeutic target and nearly 20 clinical trials targeting autophagy are in progress. Although autophagy promotes tumor progression in later stages, it plays a tumor-suppressive role early during tumorigenesis. Therefore it is crucial to determine the precise role of autophagy at different stages of salivary tumor development for future autophagy-based therapeutics. The role of autophagy is not well studied in salivary tumors, but our preliminary data, together with published reports, indicate that autophagy plays a "dual role." It reduces genetic instability early during tumorigenesis to suppress tumor formation, but then shifts its rol to provide a survival advantage for established tumors experiencing endogenous and exogenous metabolic stresses. We hypothesize that autophagy suppresses tumor initiation by inhibiting the formation of tumor-initiating cells, but acts as a key metabolic pathway for the survival of advanced salivary tumors. We will determine the role autophagy plays in suppressing submandibular tumorigenesis using a mouse model that contains a K-RasG12V transgene. The K-RasG12V can be activated to specifically induce tumors in submandibular tissue, using a Cre-recombinase that is induced by tamoxifen-feeding. We will knock-out Atg5, an essential gene for autophagy, to impair autophagy in the K-RasG12V background. Using nucleotide labeling to trace cell lineages, we will compare specific sub-populations of salivary tumor cells from autophagy- competent and autophagy-impaired K-RasG12V transgenic mice. The novel transgenic mouse model developed for this proposal will not only assist us in understanding the role of autophagy in regulating salivary tumorigenesis, but will also be invaluable as tools to screen for, and identify, novel therapeutic targets to treat these rare, but deadly cancers. Furthermore, the new knowledge will have potential relevance to the role of autophagy in regulating other oncogenic Ras-induced cancers.
描述(由申请人提供):本项目的目标是阐明自噬如何调节唾液腺肿瘤的发生和进展,以及在肿瘤发生过程中该途径如何与致癌信号通路相互作用。唾液腺肿瘤既罕见又高度多样化。由于它们的罕见性,以前对唾液腺癌的研究是有限的,到目前为止,还没有可用的类似于人类唾液腺癌病理生理学的唾液腺癌小鼠模型。因此,唾液腺肿瘤的治疗选择是有限的,个性化治疗几乎不存在,并且明显缺乏 临床前和临床验证。自噬是一种分解代谢过程,它利用细胞的溶酶体系统降解其自身的组分,包括细胞质细胞器和蛋白质。在过去的十年中,自噬通过多种机制在肿瘤的发生和发展中起着重要而复杂的作用。因此,它是一个有前途的治疗靶点,近20项针对自噬的临床试验正在进行中。虽然自噬在晚期促进肿瘤进展,但它在肿瘤发生的早期起着肿瘤抑制作用。因此,确定自噬在唾液腺肿瘤发展的不同阶段的确切作用对于未来基于自噬的治疗至关重要。自噬在唾液腺肿瘤中的作用还没有得到很好的研究,但是我们的初步数据以及已发表的报告表明自噬起着"双重作用"。“它在肿瘤发生的早期降低了遗传不稳定性以抑制肿瘤形成,但随后改变了其作用,为经历内源性和外源性代谢应激的已建立肿瘤提供了生存优势。我们假设自噬通过抑制肿瘤起始细胞的形成来抑制肿瘤起始,但作为晚期唾液腺肿瘤存活的关键代谢途径。我们将使用含有K-RasG12V转基因的小鼠模型确定自噬在抑制下颌下肿瘤发生中的作用。K-RasG12V可以被激活,以特异性地诱导下颂组织中的肿瘤,使用由他莫昔芬喂养诱导的Cre重组酶。我们将敲除自噬的必需基因Atg5,以削弱K-RasG12V背景下的自噬。使用核苷酸标记追踪细胞谱系,我们将比较来自自噬能力和自噬受损的K-RasG12V转基因小鼠的唾液肿瘤细胞的特定亚群。为这一提议开发的新型转基因小鼠模型不仅将帮助我们理解自噬在调节唾液腺肿瘤发生中的作用,而且还将作为筛选和鉴定治疗这些罕见但致命的癌症的新型治疗靶点的工具。此外,新的知识将与自噬在调节其他致癌Ras诱导的癌症中的作用具有潜在的相关性。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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David K Ann其他文献

The role of tyrosine kinase Etk/Bmx in EGF-induced apoptosis of MDA-MB-468 breast cancer cells
酪氨酸激酶 Etk/Bmx 在表皮生长因子诱导的 MDA-MB-468 乳腺癌细胞凋亡中的作用
  • DOI:
    10.1038/sj.onc.1207308
  • 发表时间:
    2003-12-15
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Kai-Yun Chen;Li-Ming Huang;Hsing-Jien Kung;David K Ann;Hsiu-Ming Shih
  • 通讯作者:
    Hsiu-Ming Shih

David K Ann的其他文献

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{{ truncateString('David K Ann', 18)}}的其他基金

Core 1: Planning and Evaluation
核心1:规划与评估
  • 批准号:
    10762163
  • 财政年份:
    2023
  • 资助金额:
    $ 23.1万
  • 项目类别:
Fatty acids and their receptors-mediated tumor metastasis and progression
脂肪酸及其受体介导的肿瘤转移和进展
  • 批准号:
    10330011
  • 财政年份:
    2020
  • 资助金额:
    $ 23.1万
  • 项目类别:
Fatty acids and their receptors-mediated tumor metastasis and progression
脂肪酸及其受体介导的肿瘤转移和进展
  • 批准号:
    9916932
  • 财政年份:
    2020
  • 资助金额:
    $ 23.1万
  • 项目类别:
Fatty acids and their receptors-mediated tumor metastasis and progression
脂肪酸及其受体介导的肿瘤转移和进展
  • 批准号:
    10549362
  • 财政年份:
    2020
  • 资助金额:
    $ 23.1万
  • 项目类别:
Yes 2 Success
是 2 成功
  • 批准号:
    10573291
  • 财政年份:
    2018
  • 资助金额:
    $ 23.1万
  • 项目类别:
Cancer Metabolism Training Program
癌症代谢培训计划
  • 批准号:
    10481834
  • 财政年份:
    2018
  • 资助金额:
    $ 23.1万
  • 项目类别:
Yes 2 Success
是 2 成功
  • 批准号:
    10000862
  • 财政年份:
    2018
  • 资助金额:
    $ 23.1万
  • 项目类别:
Yes 2 Success
是 2 成功
  • 批准号:
    9788325
  • 财政年份:
    2018
  • 资助金额:
    $ 23.1万
  • 项目类别:
Cancer Metabolism Training Program
癌症代谢培训计划
  • 批准号:
    9766219
  • 财政年份:
    2018
  • 资助金额:
    $ 23.1万
  • 项目类别:
FLOAT System to Study Salivary Gland Cancer Invasion
FLOAT 系统研究唾液腺癌侵袭
  • 批准号:
    9763563
  • 财政年份:
    2018
  • 资助金额:
    $ 23.1万
  • 项目类别:

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