@article{4e06c102f7e04252bde17cfd5d5dca8d,
title = "Fascin Controls Metastatic Colonization and Mitochondrial Oxidative Phosphorylation by Remodeling Mitochondrial Actin Filaments",
abstract = "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.",
keywords = "NSCLC, OXPHOS, actin, fascin, metastasis, metastatic colonization, mitochondria",
author = "Shengchen Lin and Chongbiao Huang and Venugopal Gunda and Jianwei Sun and Chellappan, {Srikumar P.} and Zengxun Li and Victoria Izumi and Bin Fang and John Koomen and Singh, {Pankaj K.} and Jihui Hao and Shengyu Yang",
note = "Funding Information: This work is supported, in part, by grants from the NIH ( R01CA175741 and R01CA233844 to S.Y. and R01CA210439 and R01CA216853 to P.K.S.) and the Elsa U. Pardee Foundation (to S.Y.). Proteomics is supported, in part, by the National Cancer Institute through a Moffitt{\textquoteright}s Cancer Center support grant ( P30-CA076292 ) and the Moffitt Foundation . We would also like to acknowledge the Fred & Pamela Buffett Cancer Center support grant ( P30CA036727 , NCI) for supporting shared resources. We thank Drs. J. Cleveland, H.-G. Wang, K. Aird, and H. Higgs for advice and discussions. Funding Information: This work is supported, in part, by grants from the NIH (R01CA175741 and R01CA233844 to S.Y. and R01CA210439 and R01CA216853 to P.K.S.) and the Elsa U. Pardee Foundation (to S.Y.). Proteomics is supported, in part, by the National Cancer Institute through a Moffitt's Cancer Center support grant (P30-CA076292) and the Moffitt Foundation. We would also like to acknowledge the Fred & Pamela Buffett Cancer Center support grant (P30CA036727, NCI) for supporting shared resources. We thank Drs. J. Cleveland, H.-G. Wang, K. Aird, and H. Higgs for advice and discussions. S.Y. and S.L. conceived the present study and analyzed most of the data. S.Y. and S.L. wrote the manuscript with input and support from all authors. S.L. performed most of the experiments. C.H. Z.L. and J.H. performed IHC staining and analyzed the results. V.G. and P.K.S. performed the metabolomics screening and analyzed the results. V.I. B.F. and J.K. performed the proteomics and analyzed the results. J.S. performed the initial experiment linking fascin and mtF-actin to mtDNA. S.P.C. provided critical reagents and technical support. The authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = sep,
day = "10",
doi = "10.1016/j.celrep.2019.08.011",
language = "English (US)",
volume = "28",
pages = "2824--2836.e8",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}