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

AKT-波形蛋白相互作用；

• 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
• 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

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.

项目摘要/摘要 软组织肉瘤（STS）构成了一个间充质 - 原家基因疾病的家族 可以发生在体内的任何地方。包括50多个不同的组织学亚型， STS具有几个独特的功能，包括频繁的本地复发 确定的治疗，明显的化学耐药性和频繁的转移，特别是对 肺。这些功能转化为令人沮丧的结果，特别是对于那些患者 携带高级综合核型sts组织学，主要包括 平滑肌肉瘤和高级多形性肉瘤（恶性纤维组织细胞瘤 和纤维肉瘤）。为了改善STS治疗结果，开发至关重要 利用分子脆弱性的基本点的新型药物； 但是，我们最少的理解阻碍了这一紧急目标的进展 STS前进和传播的分子决定因素的。 肿瘤细胞，包括ST，对控制生长调节的信号级联反应 恶性过程的过程和其他组成部分，例如运动，入侵， 在这些信号传导机制中诱导凋亡等。 途径在STS的生长和传播中可能尤其重要。 AKT的磷酸化是该级联的关键步骤，与 在STS组织中鉴定出STS预后受损。在人类的细胞系中 人类STS异种移植物在免疫功能不足的小鼠中生长，AKT抑制作用会干扰 随着STS的增长，也许通过破坏与波形蛋白的AKT相互作用，这是一个关键 结构蛋白也可能具有与肿瘤学的功能特性。 我们的小组显然是第一个确定Akt -Vimentin相互作用的存在的人。 我们建议研究这种互动的调节，希望了解更多有关 这些相互作用的基础机制，这种相互作用的功能意义 关于它对体内STS增殖和转移的影响，最后测试 临床前治疗方法对AKT和波形蛋白封锁，希望证明 使用人类STS异种移植小鼠模型和鼠肉瘤的临床前相关性 型号。

项目成果

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.

• DOI: 10.1371/journal.pone.0016241
• 发表时间: 2011-01-17
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Liu F;Hu X;Zimmerman M;Waller JL;Wu P;Hayes-Jordan A;Lev D;Liu K
• 通讯作者: Liu K

MiR-155 is a liposarcoma oncogene that targets casein kinase-1α and enhances β-catenin signaling.

• DOI: 10.1158/0008-5472.can-11-3027
• 发表时间: 2012-04-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Zhang P;Bill K;Liu J;Young E;Peng T;Bolshakov S;Hoffman A;Song Y;Demicco EG;Terrada DL;Creighton CJ;Anderson ML;Lazar AJ;Calin GG;Pollock RE;Lev D
• 通讯作者: Lev D