Molecular mechanisms of mechanotransduction during tumor progression

组织内的细胞不断暴露于由细胞间和细胞外基质（ECM）相互作用产生的机械信号。对机械力的反应包括通过肌动球蛋白收缩产生的相互张力、基因表达的变化和细胞外环境的重塑。细胞感知、传导和响应机械刺激的能力对器官发育和体内平衡至关重要。机械感知缺陷和机械转导改变与肿瘤的形成、进展和转移有关。因此，破译控制张力稳态的信号和效应网络是一个重要的研究方向。在过去的几年里，我们使用一个已建立的、遗传定义的果蝇肿瘤模型，揭示了协同致癌基因如何通过解除Jun n -末端激酶（JNK）信号通路对细胞力学生物学的影响。我们已经证明，由于活化的Ras与上皮细胞极性丧失的合作，克隆性肿瘤的侵袭性需要jnk依赖性的基质金属蛋白酶（MMP1）上调（Uhlirova和Bohmann， EMBO J, 2006）。最近，我们已经确定了肌动蛋白交联蛋白Filamin A/Cheerio （Cher）作为JNK信号的新靶点，将肌动蛋白细胞骨架动力学与肿瘤进展联系起来。虽然Cher对于正常果蝇的眼睛发育是必不可少的，但它通过调节肌动球蛋白的张力而成为上皮肿瘤生长和侵袭所必需的（k<e:1> lshammer和Uhlirova， J Cell Sci, 2013）。基于我们之前发表的初步数据，本研究旨在(1)利用果蝇和哺乳动物肿瘤模型确定肌动球蛋白/丝蛋白A复合物与肿瘤进展之间的联系机制；(2)研究活化的肿瘤基质如何改变机械转导并促进恶性进展；(3)利用深入的比较基因组学定义肿瘤和基质特异性表达特征。我们的工作将更好地理解癌基因诱导的机械调节网络的改变如何促进肿瘤的发生、恶性前生长和转移的进展。我们相信，通过对肿瘤细胞和组织力学生物学的新见解，拟议的项目将对生物医学研究具有普遍的重要性。

Cells within tissues are continuously exposed to mechanical cues generated by cell-cell and cell-extracellular matrix (ECM) interactions. Responses to mechanical forces include exertion of reciprocal tension through actomyosin contraction, changes in gene expression, and remodeling of the extracellular environment. The ability of cells to sense, transduce and respond to mechanical stimuli is crucial for organ development and homeostasis. Defects in mechanosensing and altered mechanotransduction have been linked to tumor formation, progression and metastasis. Deciphering the signaling and effector network that controls tensional homeostasis is, therefore, of major interest. Over the past years, our work using an established, genetically defined Drosophila tumor model has unraveled how cooperating oncogenes impact on cellular mechanobiology through deregulation of the Jun N-terminal kinase (JNK) signaling pathway. We have shown that invasiveness of clonal tumors, resulting from cooperation of activated Ras with loss of epithelial cell polarity, requires JNK-dependent up-regulation of a Matrix metalloprotease (MMP1) (Uhlirova and Bohmann, EMBO J, 2006). Recently, we have identified the actin cross-linking protein Filamin A/Cheerio (Cher) as a novel target of JNK signaling that links actin cytoskeleton dynamics to tumor progression. Although Cher is dispensable for normal Drosophila eye development, it becomes required in the epithelial tumors for their growth and invasiveness through regulating actomyosin tension (Külshammer and Uhlirova, J Cell Sci, 2013). Building on our previously published and preliminary data, this proposal aims (1) to identify mechanisms that link the actomyosin/Filamin A complex to tumor progression using Drosophila and mammalian tumor models, (2) to investigate how activated tumor stroma alters mechanotransduction and contributes to malignant progression, and (3) to define tumor- and stroma-specific expression signatures using in-depth comparative genomics. Our work will provide better understanding of how oncogene-induced alteration of the mechanoregulatory network contributes to tumor initiation, pre-malignant growth, and progression towards metastases. We believe that by bringing new insights into tumor cell and tissue mechanobiology, the proposed project will be of general importance for biomedical research.