Targeting glycocalyx-mediated mechanisms of tumor metastasis

癌细胞从原发肿瘤迁移到远处器官的能力是最终的 癌症的死亡原因。虽然许多分子和粘附途径已被确定， 仍然没有限制患者转移的有效策略。这在很大程度上是由于我们缺乏 了解启动细胞侵入周围组织和血管的信号。前几 我们的工作表明，来自流动的组织间液的机械力引起了细胞表型的深刻变化， 癌细胞这些力由细胞糖萼传递，并影响细胞迁移、MMP活性和细胞增殖。 粘附分子表达。我们认为，糖萼-凭借其在机械传导中的作用- 代表了抑制癌症迁移和转移的新的和有前途的靶点。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组分， 负责机械诱导细胞侵袭的途径，然后在小鼠中靶向这些机制。 肾癌模型。Aim 1a将利用基因沉默去除糖萼的特定成分， 确定参与流动诱导的转移激活的关键结构，目标1b将检查 细胞内信号通路下游的糖萼，可能是针对抑制入侵。在Aim中 2，我们将使用小鼠肾癌模型来确定糖萼成分如何有助于 局部血管内渗（目标2a）和远处转移（目标2b）。关键的糖萼 成分和目标确定后，我们将使用药物干预来阻断转移（目的 2c）。最后，我们将改变原位小鼠肾癌的间质血流，以证明诱导 在体内环境中通过流动转移（目的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.