A novel role of fascin in cancer metastasis

肌成束蛋白在癌症转移中的新作用

• 批准号: 10532747
• 负责人: Shengyu Yang
• 金额: $ 35.09万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-04 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532747
• 关键词: 5' -AMP-activated protein kinase; Actin-Binding Protein; Actins; Aggressive Clinical Course; Anoikis; Automobile Driving; Biogenesis; Bundling; CRISPR/Cas technology; Cancer Control; Cancer Model; Carcinoma; Cells; Cessation of life; Chemoresistance; Complex; Coupled; Cytoskeleton; Data; Disease; Disseminated Malignant Neoplasm; Distant; Genetic; Goals; Homeostasis; Invaded; Lung Adenocarcinoma; Maintenance; Malignant Neoplasms; Mechanics; Mediating; Mediator; Metabolic; Metastatic/Recurrent; Microfilaments; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Organ; Pathway interactions; Patients; Play; Primary Neoplasm; Process; Recurrence; Regulation; Resistance; Respiration; Role; Signal Transduction; Site; Stress; Suspensions; Testing; Transcription Coactivator; Xenograft procedure; cancer cell; cancer stem cell; cancer type; cell motility; constriction; crosslink; fascin; formin-2; improved; inhibitor; insight; lung cancer cell; mouse model; novel; novel strategies; overexpression; pharmacologic; prevent; respiratory; self-renewal; sensor; stem cell self renewal; stem-like cell; stemness; success; transcription factor; tumor progression; tumorigenesis

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.

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向远处器官的扩散， 以及扩散的转移细胞的扩张以形成继发性肿瘤。众所周知， 肌动蛋白细胞骨架经常失调，以促进癌细胞的运动性、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后传播作用在很大程度上是由细胞骨架的结构决定的。 未开发的成束蛋白是转移性癌症中最常见的过表达肌动蛋白结合蛋白，其 过度表达与转移性疾病、侵袭性临床病程和较短生存期一致相关 在不同的癌症类型中。通常认为，肌成束蛋白通过增强肿瘤细胞的增殖能力来驱动癌症转移。 肌动蛋白细胞骨架和促进细胞运动。在NSCLC模型中进行的初步研究中， 发现了肌成束蛋白在促进转移性定植和扩张以及增强癌症中的新作用 通过重塑线粒体肌动蛋白丝来诱导细胞干细胞。我们认为，肌成束蛋白增强了自我更新， 通过新型fascin-mitochondrial-AMPK-YAP/TAZ的癌症干细胞样细胞和转移性扩增 通路我们将在这些令人兴奋的初步发现的基础上，研究肌成束蛋白的功能作用， 介导的线粒体肌动蛋白丝的重塑。然后，我们将定义AMPK的角色- 雅普/TAZ通路在Fascin介导的癌细胞干细胞性增强中的作用在目标3中， 确定fascin和线粒体肌动蛋白丝在fascin介导的NSCLC中的新线粒体作用 转移，并将探索通过以下方法抑制癌细胞干细胞和转移复发的可行性： 靶向肌成束蛋白。拟议的研究的成功将导致我们对这一问题的理解发生范式转变。 肌动蛋白细胞骨架失调的转移进展，并将潜在地提供新的途径，以防止 NSCLC转移性复发。

项目成果

Spatiotemporal regulation of store-operated calcium entry in cancer metastasis.

• DOI: 10.1042/bst20210307
• 发表时间: 2021-12-17
• 期刊: Biochemical Society transactions
• 影响因子: 3.9

Mitochondrial Calcium Uniporter Drives Metastasis and Confers a Targetable Cystine Dependency in Pancreatic Cancer.

• DOI: 10.1158/0008-5472.can-21-3230
• 发表时间: 2022-06-15
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Wang, Xiuchao;Li, Yunzhan;Li, Zekun;Lin, Shengchen;Wang, Hongwei;Sun, Jianwei;Lan, Chungen;Wu, Liangliang;Sun, Dongxiao;Huang, Chongbiao;Singh, Pankaj K.;Hempel, Nadine;Trebak, Mohamed;DeNicola, Gina M.;Hao, Jihui;Yang, Shengyu
• 通讯作者: Yang, Shengyu

How does fascin promote cancer metastasis?

• DOI: 10.1111/febs.15484
• 发表时间: 2021-03
• 期刊: The FEBS journal
• 作者: Lin S;Taylor MD;Singh PK;Yang S
• 通讯作者: Yang S

Serum insulin-like growth factor binding protein 2 levels as biomarker for pancreatic ductal adenocarcinoma-associated malnutrition and muscle wasting.

血清胰岛素样生长因子结合蛋白 2 水平作为胰腺导管腺癌相关营养不良和肌肉萎缩的生物标志物。

• DOI: 10.1002/jcsm.12692
• 发表时间: 2021-06
• 期刊: Journal of cachexia, sarcopenia and muscle
• 作者: Dong J;Yu J;Li Z;Gao S;Wang H;Yang S;Wu L;Lan C;Zhao T;Gao C;Liu Z;Wang X;Hao J
• 通讯作者: Hao J

Fascin promotes lung cancer growth and metastasis by enhancing glycolysis and PFKFB3 expression.

• DOI: 10.1016/j.canlet.2021.07.025
• 发表时间: 2021-10-10
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Lin S;Li Y;Wang D;Huang C;Marino D;Bollt O;Wu C;Taylor MD;Li W;DeNicola GM;Hao J;Singh PK;Yang S
• 通讯作者: Yang S