A novel role of fascin in cancer metastasis

我们的长期目标是确定法辛控制癌症转移和 进步。癌症转移涉及癌细胞从原发肿瘤向远处器官的扩散， 以及播散性转移细胞的扩张形成继发性肿瘤。已经很好地确定了 在转移过程中，肌动蛋白细胞骨架经常被失控以促进癌细胞的运动和侵袭。 传播。然而，肌动蛋白细胞骨架在肿瘤转移中的后扩散作用主要是 未被开发的。Fasin是转移性癌症中最常见的过度表达的肌动蛋白结合蛋白，其 过度表达与转移性疾病、侵袭性临床病程和较短的生存期一致相关 跨越不同的癌症类型。人们普遍认为，筋膜蛋白通过增强肿瘤细胞内的 肌动蛋白与细胞骨架和促进细胞运动。在非小细胞肺癌模型的初步研究中，我们 发现了一种新的发束素在促进转移定植和扩张以及增强肿瘤中的作用 通过重塑线粒体肌动蛋白细丝实现细胞干化。我们认为，法辛可以促进自我更新。 通过一种新的Fasin-线粒体-AMPK-YAP/TAZ对肿瘤干细胞和转移扩展的影响 路径。我们将在这些令人兴奋的初步发现的基础上，研究筋膜蛋白的功能作用。 在AIM 1中介导的线粒体肌动蛋白细丝的重塑。然后我们将确定AMPK- YAP/TAZ通路在Fasin介导的肿瘤细胞干性增强中的作用 确定筋膜蛋白和线粒体肌动蛋白细丝在非小细胞肺癌中的新作用 转移，并将探索通过以下途径抑制癌细胞干细胞分化和转移复发的可行性 瞄准法辛。拟议研究的成功将导致我们对 转移进展中肌动蛋白细胞骨架的失调，并将潜在地提供新的途径来预防 非小细胞肺癌转移复发。

Our long-term goals are to define the molecular mechanisms by which fascin controls cancer metastasis and progression. Cancer metastasis involves the dissemination of cancer cells from primary tumor to distant organ, and the expansion of disseminated metastatic cells to form secondary tumor. It has been well established that the actin cytoskeleton is frequently dysregulated to promote cancer cell motility, invasiveness during metastatic dissemination. However, the post-dissemination role of the actin cytoskeleton in cancer metastasis is largely unexplored. Fascin is the most frequently overexpressed actin binding protein in metastatic cancer, and its overexpression is uniformly associated with metastatic disease, aggressive clinical course and shorter survival across different cancer types. It is generally thought that fascin drives cancer metastasis by strengthening the actin cytoskeleton and promoting cell motility. In preliminary studies conducted in NSCLC models, we discovered a novel role for fascin in promoting metastatic colonization and expansion and augmenting cancer cell stemness by remodeling mitochondrial actin filaments. We propose that fascin enhances the self-renewal of cancer stem-like cell and metastatic expansion through a novel fascin-mitochondria-AMPK-YAP/TAZ pathway. We will build on these exciting preliminary findings to investigate the functional role of fascin- mediated remodeling of mitochondrial actin filaments in Aim 1. We will then define the role of the AMPK- YAP/TAZ pathway in fascin-mediated augmentation of cancer cell stemness in Aim 2. In Aim 3 we will determine the novel mitochondrial role of fascin and mitochondrial actin filaments in fascin-mediated NSCLC metastasis, and will explore the feasibility to inhibit cancer cell stemness and metastatic recurrence by targeting fascin. The success of proposed studies will cause a paradigm-shift in our understanding of the dysregulated actin cytoskeleton in metastatic progression, and will potentially provide novel avenues to prevent NSCLC metastatic recurrence.