Fascin Controls Metastatic Colonization and Mitochondrial Oxidative Phosphorylation by Remodeling Mitochondrial Actin Filaments
Shengchen Lin,
Chongbiao Huang,
Venugopal Gunda,
Jianwei Sun,
Srikumar P. Chellappan,
Zengxun Li,
Victoria Izumi,
Bin Fang,
John Koomen,
Pankaj K. Singh,
Jihui Hao,
Shengyu Yang
Affiliations
Shengchen Lin
Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA
Chongbiao Huang
Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
Venugopal Gunda
Eppley Institute for Research in Cancer and Allied Diseases, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
Jianwei Sun
Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA; State Key Laboratory of Conservation and Utilization of Bio-Resources in Yunnan and Center for Life-Sciences, School of Life Sciences, Yunnan University, Kunming, China
Srikumar P. Chellappan
Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
Zengxun Li
Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
Victoria Izumi
Department of Molecular Oncology and Proteomics Core, H. Lee Moffitt Cancer Center, Tampa, FL, USA
Bin Fang
Department of Molecular Oncology and Proteomics Core, H. Lee Moffitt Cancer Center, Tampa, FL, USA
John Koomen
Department of Molecular Oncology and Proteomics Core, H. Lee Moffitt Cancer Center, Tampa, FL, USA
Pankaj K. Singh
Eppley Institute for Research in Cancer and Allied Diseases, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
Jihui Hao
Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
Shengyu Yang
Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA; Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Corresponding author
Summary: The deregulation of the actin cytoskeleton has been extensively studied in metastatic dissemination. However, the post-dissemination role of the actin cytoskeleton dysregulation is poorly understood. Here, we report that fascin, an actin-bundling protein, promotes lung cancer metastatic colonization by augmenting metabolic stress resistance and mitochondrial oxidative phosphorylation (OXPHOS). Fascin is directly recruited to mitochondria under metabolic stress to stabilize mitochondrial actin filaments (mtF-actin). Using unbiased metabolomics and proteomics approaches, we discovered that fascin-mediated mtF-actin remodeling promotes mitochondrial OXPHOS by increasing the biogenesis of respiratory Complex I. Mechanistically, fascin and mtF-actin control the homeostasis of mtDNA to promote mitochondrial OXPHOS. The disruption of mtF-actin abrogates fascin-mediated lung cancer metastasis. Conversely, restoration of mitochondrial respiration by using yeast NDI1 in fascin-depleted cancer cells is able to rescue lung metastasis. Our findings indicate that the dysregulated actin cytoskeleton in metastatic lung cancer could be targeted to rewire mitochondrial metabolism and to prevent metastatic recurrence. : Lin et. al. show that fascin, a pro-metastasis actin-bundling protein, promotes mitochondrial oxidative phosphorylation and metabolic stress resistance in lung adenocarcinoma by remodeling mitochondrial actin filaments and regulating the homeostasis of mitochondrial DNA. Keywords: fascin, actin, mitochondria, NSCLC, metastasis, metastatic colonization, OXPHOS
