Targeting glycocalyx-mediated mechanisms of tumor metastasis

癌细胞离开原发肿瘤并在远处器官定居的能力是终极的。 癌症的致死原因。尽管已经确定了许多分子和黏附途径， 目前还没有有效的策略来限制患者的转移。这在很大程度上是因为我们缺乏 了解启动细胞侵入周围组织和血管的信号。在以前的 工作中，我们证明了来自流动的间质流体的机械力导致了 癌细胞。这些力通过细胞糖基化传递，影响细胞迁移、基质金属蛋白酶活性和 黏附分子的表达。我们认为，由于其在机械转导中的作用，糖萼-- 为抑制肿瘤的转移和转移提供了一个新的靶点。在这个项目中，我们将 使用体外分析和体内模型的紧密结合来确定成分和 负责机械诱导的细胞入侵的途径，然后在小鼠中靶向这些机制 肾癌模型的建立。Aim 1a将使用基因沉默来移除糖萼的特定成分，以 确定与血流诱导的转移激活有关的关键结构，目标1b将研究 糖萼下游的细胞内信号通路可能是抑制侵袭的靶点。在AIM 2，我们将使用肾癌的小鼠模型来确定糖萼成分是如何对 局部血管内转移(目标2a)和远处转移(目标2b)。带着关键的糖萼 确定成分和靶点后，我们将使用药物干预来阻断转移(目的 2C)。最后，我们将改变小鼠原位肾癌的间质血流，以证明诱导 活体环境下的血流转移(目标3)。这些研究有可能揭示 启动肿瘤转移的机制，并将打开新的治疗策略的大门 机械生物学信号通路。

The ability of cancer cells to migrate away from the primary tumor and colonize distant organs is the ultimate cause of mortality in cancer. Although many of the molecular and adhesion pathways have been identified, there is still no effective strategy for limiting metastasis in patients. This is in large part due to our lack of understanding of the signals that initiate cell invasion into the surrounding tissue and blood vessels. In previous work, we showed that mechanical forces from flowing interstitial fluid cause profound phenotypic changes in cancer cells. These forces are transmitted by the cell glycocalyx and influence cell migration, MMP activity and adhesion molecule expression. We propose that the glycocalyx– by virtue of its role in mechanotransduction— represents a new and promising target for inhibiting cancer migration and metastasis. In this project, we will use a tightly-integrated combination of in vitro analyses and in vivo models to determine the components and pathways responsible for mechanically-induced cell invasion, and then target these mechanisms in a mouse model of renal carcinoma. Aim 1a will use gene silencing to remove specific components of the glycocalyx to identify key structures involved in flow-induced activation of metastasis, and Aim 1b will examine the intracellular signaling pathways downstream of the glycocalyx that might be targeted to inhibit invasion. In Aim 2, we will use a mouse model of renal carcinoma to determine how the glycocalyx components contribute to local intravasation into the vasculature (Aim 2a) and distant metastasis (Aim 2b). With the key glycocalyx components and targets identified, we will then use pharmacological interventions to block metastasis (Aim 2c). Finally, we will alter interstitial flow in an orthotopic mouse renal carcinoma to demonstrate the induction of metastasis by flow in the in vivo setting (Aim 3). These studies have the potential to uncover the fundamental mechanisms that initiate tumor metastasis, and will open the door to new therapeutic strategies that exploit mechanobiological signaling pathways.