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

项目总结/摘要 软组织肉瘤（STS）是一种间叶源性恶性肿瘤家族， 可以发生在身体的任何地方。包括50多种不同的组织学亚型， STS有几个共同的特点，包括频繁的局部复发后， 明确的治疗，明显的化疗耐药性，和频繁的转移，特别是对 肺这些特点转化为一个令人沮丧的结果，特别是对那些病人来说， 具有高度复杂的核型STS组织学，主要包括 平滑肌肉瘤和高度多形性肉瘤（恶性纤维组织细胞瘤 和纤维肉瘤）。为了改善STS治疗结果， 利用分子脆弱性的潜在STS点的新型药物; 然而，由于我们缺乏理解，在实现这一紧迫目标方面进展受到阻碍 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 过程和恶性过程的其他成分，如运动，侵袭， 在这些信号传导机制中，AKT激酶 途径可能在STS生长和传播中特别重要。 AKT的磷酸化是这一级联反应中的关键步骤， 当在STS组织中鉴定时，STS预后受损。在人STS细胞系中， 在免疫缺陷小鼠中生长的人STS异种移植物，AKT抑制干扰 随着STS的增长，也许是通过破坏AKT与波形蛋白的相互作用， 也可能具有肿瘤学相关功能特性结构蛋白。 我们的小组显然是第一个确定AKT -波形蛋白相互作用的存在。 我们建议研究这种相互作用的调节，希望更多地了解 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增殖和转移在体内，并最终测试 AKT和波形蛋白阻断的临床前治疗方法，希望证明 使用人STS异种移植小鼠模型和鼠肉瘤的临床前相关性 模型

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.