A novel role of fascin in cancer metastasis

我们的长期目标是确定肌成束蛋白控制癌症转移的分子机制 进展。癌症转移涉及癌细胞从原发肿瘤扩散到远处器官， 以及播散性转移细胞的扩张形成继发性肿瘤。已经确定的是 肌动蛋白细胞骨架经常失调，以促进癌细胞的运动性和转移过程中的侵袭性 传播。然而，肌动蛋白细胞骨架在癌症转移中的播散后作用很大程度上是 未经探索。肌成束蛋白是转移性癌症中最常过度表达的肌动蛋白结合蛋白，其 过度表达一致与转移性疾病、侵袭性临床病程和较短的生存期相关 跨越不同的癌症类型。人们普遍认为肌成束蛋白通过增强肌成束蛋白来驱动癌症转移。 肌动蛋白细胞骨架并促进细胞运动。在 NSCLC 模型中进行的初步研究中，我们 发现肌成束蛋白在促进转移定植和扩张以及增强癌症方面的新作用 通过重塑线粒体肌动蛋白丝来实现细胞干细胞性。我们建议肌成束蛋白增强自我更新 通过新型肌成束蛋白-线粒体-AMPK-YAP/TAZ 控制癌症干细胞样细胞和转移扩张 途径。我们将在这些令人兴奋的初步发现的基础上研究成束蛋白的功能作用 目标 1 中介导的线粒体肌动蛋白丝重塑。然后我们将定义 AMPK-的作用 在目标 2 中，YAP/TAZ 通路通过肌成束蛋白介导增强癌细胞干性。在目标 3 中，我们将 确定肌成束蛋白和线粒体肌动蛋白丝在肌成束蛋白介导的 NSCLC 中的新线粒体作用 转移，并将探索通过抑制癌细胞干细胞和转移复发的可行性 靶向肌成束蛋白。拟议研究的成功将导致我们对这一问题的理解发生范式转变 肌动蛋白细胞骨架在转移过程中失调，并有可能提供新的途径来预防 NSCLC 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.