Regulation of collagen linearization during cancer progression and metastasis

转移占癌症相关死亡的绝大多数，但其潜在机制是 不完全理解。在肿瘤进展过程中，肿瘤微环境的广泛重塑 发生并促进转移。特别是，细胞外含量最丰富的胶原蛋白的线性化 肿瘤中的基质(ECM)蛋白被认为是侵袭性乳腺癌的标志，并与 预后不良。在细胞水平上，线性化的胶原束促进肿瘤细胞的侵袭和 通过提供肿瘤细胞可以容易迁移的轨迹来实现转移。细胞产生的机械张力具有 已被认为有助于胶原重塑，但仍不清楚这是否是唯一的 胶原线性化的建立机制或其他机制是否也起重要作用 在这一过程中的角色。我们最近的研究表明，癌细胞分泌能够线性化胶原蛋白的因子。 与细胞产生的机械力无关。具体地说，我们发现肿瘤细胞分泌因子 WISP1(CCN4)促进胶原线性化，促进肿瘤细胞的侵袭和转移。然而，蜂窝和 WISP1线性化胶原并促进转移的分子机制尚不完全 明白了。为了揭示这些机制，我们将1)定义转移级联的具体步骤 受WISP1的影响，2)确定WISP1调节胶原的分子机制 线性化并促进肿瘤细胞侵袭；3)试验阻断WISP1‘S功能的治疗方法 并防止肿瘤转移。这将通过对乳腺癌进展进行详细分析来实现 并在小鼠模型和体外侵袭试验中进行转移。我们研究的中心也是使用 扫描电子显微镜与体内多光子荧光和二次谐波产生 显微镜观察体外和体内细胞外基质构筑的变化。在全球范围内，这些研究将阐明 胶原纤维线性化的基本机制和测试创新的治疗方法以限制 通过使胶原蛋白结构正常化而转移。

Metastasis accounts for the vast majority of cancer-related deaths but its underlying mechanisms are incompletely understood. During tumor progression extensive remodeling of the tumor microenvironment occurs and facilitates metastasis. In particular, linearization of collagen, one of the most abundant extracellular matrix (ECM) proteins in tumors, is recognized as a hallmark of aggressive breast cancers and is associated with poor prognosis. At the cellular level, bundles of linearized collagen facilitate tumor cell invasion and metastasis by providing tracks on which tumor cells can easily migrate. Cell-generated mechanical tension has been proposed to contribute to collagen remodeling, but it remained unknown whether this is the sole mechanism by which collagen linearization is established or whether other mechanisms also play prominent roles in this process. Our recent studies revealed that cancer cells secrete factors that can linearize collagen independently of cell-generated mechanical forces. Specifically, we found that the tumor cell-secreted factor WISP1 (CCN4) promotes collagen linearization, tumor cell invasion and metastasis. However, the cellular and molecular mechanisms by which WISP1 linearizes collagen and promote metastasis remain incompletely understood. To uncover these mechanisms we will 1) define the specific steps of the metastatic cascade that are impacted by WISP1, 2) determine the molecular mechanisms by which WISP1 regulates collagen linearization and promotes tumor cell invasion, and 3) test therapeutic modalities to block WISP1’s function and prevent metastasis. This will be achieved by performing detailed analyses of breast cancer progression and metastasis in mouse models and in vitro invasion assays. Central to our studies is also the use of scanning electron microscopy and intravital multiphoton fluorescence and second harmonic generation microscopy to visualize alterations in ECM architecture in vitro and in vivo. Globally, these studies will elucidate fundamental mechanisms of collagen fiber linearization and test innovative therapeutic approaches to limit metastasis by normalizing collagen architecture.