3D-Adhesion Stromagenesis in Cancer Permissiveness

描述（由申请人提供）：肿瘤微环境在肿瘤发生和进展中起着至关重要的作用。肿瘤通过调节成纤维基质细胞在肿瘤发展过程中改变基质细胞外基质（ECM）的形貌和分子组成。基质的这些物理和生物化学改变影响幼稚基质细胞的特性以变得活化并促进基质活化，从而促进癌细胞进展。肿瘤和间质之间的重要相互作用意味着，原则上，有可能靶向调节肿瘤诱导的间质活化的信号通路，从而抑制肿瘤发生。 我们已经开发了3D体外和离体系统，所述系统包括在3D中接种在衍生自基质成纤维细胞的基质中或脱细胞的致瘤组织ECM中的细胞。使用这些系统，我们不仅观察到基质基质随着肿瘤的发展而被修饰，而且观察到肿瘤基质对于诱导正常成纤维细胞显示肿瘤相关成纤维细胞的特性是必要且足够的。在过去，我们表明，整合素依赖性信号通路的改变是至关重要的肿瘤促进基质的发展，肿瘤细胞的侵袭可以通过靶向基本基质成分抑制。与一组专注于肾癌的临床研究人员合作，我们开发了广泛的资源来剖析这种疾病中的基质-肿瘤相互作用。初步结果：一种蛋白质组学特征，其定义了一组蛋白质，包括赖氨酰氧化酶（LOX）和骨膜蛋白，其在肿瘤相关ECM中特异性上调，并鉴定了palladin基质表达作为肾癌中肿瘤预后的高度预测因子。在这项研究中，我们建议： 1.检验肿瘤相关ECM的特定结构和生物化学成分协同诱导幼稚成纤维细胞表型转换的假设。 2.确定palladin在由肿瘤相关但非正常ECM诱导的特异性整合素串扰调节的表型转换中的作用。 3.评估间质活化在人肾细胞癌（RCC）中的临床意义。 公共卫生相关性：这项研究的结果将有助于揭示一些负责肿瘤恶性循环的机制，这些恶性循环维持基质活化，进而刺激肿瘤进展。该研究将强调评估间充质基质进展的临床相关性，并且它可以揭示防止基质进展并因此阻止肿瘤发生的可能靶点。

DESCRIPTION (provided by applicant): The tumor microenvironment plays a crucial role in tumor development and progression. Tumors alter the topography and molecular composition of stromal extracellular matrix (ECM) by regulation of fibroblastic stromal cells during tumor development. These physical and biochemical alterations of the stroma affect the properties of naive stromal cells to become activated and fuel stromal activation thus promoting cancer cell progression. The vital interplay between tumor and stroma means that, in principle, it is possible to target signaling pathways that regulate tumor-induced stroma activation and thereby contain tumorigenesis. We have developed 3D in vitro and an ex vivo systems comprising cells plated in 3D in matrices derived from stromal fibroblasts or in decellularized tumorigenic tissue ECMs. Using these systems, we have not only observed that stromal matrices are modified as the tumor develops but that tumor matrices are both necessary and sufficient to induce normal fibroblasts to display properties characteristic of tumor-associated fibroblasts. In the past we showed that alterations in integrin-dependent signaling pathways are critical to the development of tumor-promoting stroma and that tumor cell invasion can be repressed by targeting fundamental stroma components. In collaboration with a team of clinical researchers focused on kidney cancer, we have developed extensive resources to dissect stromal-tumor interactions in this disease. Preliminary results rendered: a proteomic signature that has defined a group of proteins including lysyl oxidase (LOX), and periostin as specifically upregulated in tumor-associated ECM, and identified palladin stromal expression as highly predictive of tumor prognosis in renal cancer. In this study we propose to: 1. Test the hypothesis that specific structural and biochemical components of the tumor-associated ECM collaborate to induce a phenotypic switch in naive fibroblasts. 2. Establish the role for palladin in the phenotypic switch regulated by specific integrin crosstalk induced by tumor-associated but not normal ECM. 3. Assess the clinical importance of stromal activation in human renal cell carcinoma (RCC). PUBLIC HEALTH RELEVANCE: Results stemming from this study will facilitate uncovering some of the mechanisms responsible for the tumor fueling vicious cycle which maintains stroma activation and in turn incites tumor progression. The study will emphasize the clinical relevance of assessing the progression of mesenchymal stroma, and it could reveal possible targets to prevent stroma progression and consequently stall tumorigenesis.