AKT-Vimentin interaction; a potential role in soft tissue sarcoma progression and

AKT-波形蛋白相互作用；

基本信息

批准号：
8458614
负责人：
MENASHE BARELI
金额：
$ 29.14万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8458614
关键词：
AKT inhibition Accounting Address Adhesions Affect Aneuploidy Apoptosis Architecture Attention Automobile Driving Back Behavior Binding Carcinoma Cell Cycle Arrest Cell Line Cell physiology Cells Chromosomal translocation Clinical Complex Cytogenetics Data Disease Distant Environment Epithelial Etiology Family Goals Growth Heterogeneity Histology Human Human Cell Line Immigration In Vitro Induction of Apoptosis Intermediate Filaments Investigation Karyotype Knowledge Laboratories Learning Lung Malignant - descriptor Malignant Fibrous Histiocytoma Malignant Neoplasms Mesenchymal Modeling Molecular Molecular Profiling Mus Neoplasm Metastasis Outcome Pathway interactions Patients Phosphorylation Phosphotransferases Preclinical Testing Process Property Proto-Oncogene Proteins c-akt Recurrence Regulation Research Resistance Role Sampling Secondary to Signal Pathway Signal Transduction Structural Protein Therapeutic Tissues Translating Tumor Markers Undifferentiated Vimentin Xenograft Model Xenograft procedure abstracting base cancer cell cell motility epithelial to mesenchymal transition fibrosarcoma improved in vivo interest leiomyosarcoma migration mouse model neoplastic cell novel novel therapeutic intervention outcome forecast pre-clinical protein kinase C kinase sarcoma soft tissue stem treatment center tumor tumorigenic

项目摘要

Project Summary/Abstract Soft tissue sarcomas (STS) constitute a family of mesenchymal -origin malignancies that can occur anywhere in the body. Comprising more than 50 distinct histological subtypes, STS share several distinctive features that include frequent local recurrence after definitive therapy, marked chemoresistance, and frequent metastasis, especially to the lungs. These features translate to a dismal outcome, especially for those patients harboring high grade complex karyotype STS histologies, consisting mainly of leiomyosarcoma and high grade pleomorphic sarcoma ( malignant fibrous histiocytoma and fibrosarcoma). To improve STS therapeutic outcome it will be critical to develop novel agents that capitalize on underlying STS points of molecular vulnerability; however, progress towards this urgent goal are hampered by our minimal understanding of the molecular determinants underlying STS prog ression and dissemination. Tumor cells, including STS, respond to signaling cascades that control growth regulation processes and other components of the malignant process such as motility, invasion, induction of apoptosis, etc. Among theses signaling mechanisms, the AKT kinase pathway may be particularly important in STS growth and dissemination. Phosphorylation of AKT is a critical step in this cascade, had has been associated with impaired STS prognosis when identified in STS tissues. In human STS cell lines and human STS xenografts growing in immuno -incompetent mice, AKT inhibition interferes with STS growth, perhaps by disrupting AKT interaction with vimentin, a critical structural protein that may also have oncologically-relevant functional properties. Our group is apparently the first to identify the existence of AKT -vimentin interactions. We propose to study the regulation of this interaction, hoping to learn more about the mechanisms underlying these interactions, the functional significance of this interaction regarding how it impacts on STS proliferation and metastasis in vivo, and finally to test preclinical therapeutic approaches to AKT and vimentin blockade, hoping to demonstrate preclinical relevance using human STS xenograft mouse models and murine sarcoma models.

项目概要/摘要软组织肉瘤 (STS) 是一类间质来源的恶性肿瘤，可发生在身体的任何部位。包含 50 多种不同的组织学亚型， STS 有几个显着特征，包括术后频繁局部复发。根治性治疗、显着的化疗耐药性和频繁的转移，尤其是向肺。这些特征转化为令人沮丧的结果，特别是对于那些患者具有高级复杂核型 STS 组织学，主要包括平滑肌肉瘤和高级别多形性肉瘤（恶性纤维组织细胞瘤和纤维肉瘤）。为了改善 STS 治疗效果，开发利用分子脆弱性的潜在 STS 点的新型药物；然而，我们对这一紧迫目标的了解有限，阻碍了这一进展 STS 进展和传播的分子决定因素。肿瘤细胞（包括 STS）对控制生长调节的信号级联反应作出反应过程和恶性过程的其他组成部分，例如运动、侵袭、诱导细胞凋亡等。在这些信号机制中，AKT 激酶途径可能在 STS 的生长和传播中特别重要。 AKT 磷酸化是该级联中的关键步骤，与在 STS 组织中发现时，STS 预后受损。在人类 STS 细胞系和人类 STS 异种移植物在免疫功能低下的小鼠中生长，AKT 抑制会干扰随着 STS 的生长，可能是通过破坏 AKT 与波形蛋白的相互作用来实现的，波形蛋白是一个关键的结构蛋白也可能具有肿瘤学相关的功能特性。我们的小组显然是第一个发现 AKT -vimentin 相互作用存在的小组。我们建议研究这种相互作用的调控，希望能更多地了解这些相互作用的机制、这种相互作用的功能意义关于它如何影响STS体内增殖和转移，最后进行测试 AKT 和波形蛋白阻断的临床前治疗方法，希望能够证明使用人类 STS 异种移植小鼠模型和鼠肉瘤的临床前相关性模型。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Heterogeneity and immunophenotypic plasticity of malignant cells in human liposarcomas.

DOI：
10.1016/j.scr.2013.04.011
发表时间：
2013-09
期刊：
STEM CELL RESEARCH
影响因子：
1.2
作者：
Zhang, Yan;Young, Eric D.;Bill, Katelynn;Belousov, Roman;Peng, Tingsheng;Lazar, Alexander J.;Pollock, Raphael E.;Simmons, Paul J.;Lev, Dina;Kolonin, Mikhail G.
通讯作者：
Kolonin, Mikhail G.

The expression of c-Met pathway components in unclassified pleomorphic sarcoma/malignant fibrous histiocytoma (UPS/MFH): a tissue microarray study.

c-Met 通路成分在未分类的多形性肉瘤/恶性纤维组织细胞瘤 (UPS/MFH) 中的表达：组织微阵列研究。

DOI：
10.1111/j.1365-2559.2011.03946.x
发表时间：
2011
期刊：
Histopathology
影响因子：
6.4
作者：
Lahat,Guy;Zhang,Pingyu;Zhu,Quan-Sheng;Torres,Keila;Ghadimi,Markus;Smith,KerringtonD;Wang,Wei-Lien;Lazar,AlexanderJ;Lev,Dina
通讯作者：
Lev,Dina

Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies.

DOI：
10.1371/journal.pone.0010105
发表时间：
2010-04-16
期刊：
PloS one
影响因子：
3.7
作者：
Lahat G;Zhu QS;Huang KL;Wang S;Bolshakov S;Liu J;Torres K;Langley RR;Lazar AJ;Hung MC;Lev D
通讯作者：
Lev D

TNFα cooperates with IFN-γ to repress Bcl-xL expression to sensitize metastatic colon carcinoma cells to TRAIL-mediated apoptosis.