@article{4795691e4f844c2593dd65ad8fbe5081,
title = "Mechano-induced cell metabolism promotes microtubule glutamylation to force metastasis",
abstract = "Mechanical signals from the tumor microenvironment modulate cell mechanics and influence cell metabolism to promote cancer aggressiveness. Cells withstand external forces by adjusting the stiffness of their cytoskeleton. Microtubules (MTs) act as compression-bearing elements. Yet how cancer cells regulate MT dynamic in response to the locally constrained environment has remained unclear. Using breast cancer as a model of a disease in which mechanical signaling promotes disease progression, we show that matrix stiffening rewires glutamine metabolism to promote MT glutamylation and force MT stabilization, thereby promoting cell invasion. Pharmacologic inhibition of glutamine metabolism decreased MT glutamylation and affected their mechanical stabilization. Similarly, decreased MT glutamylation by overexpressing tubulin mutants lacking glutamylation site(s) decreased MT stability, thereby hampering cancer aggressiveness in vitro and in vivo. Together, our results decipher part of the enigmatic tubulin code that coordinates the fine-tunable properties of MT and link cell metabolism to MT dynamics and cancer aggressiveness.",
keywords = "breast cancer, cancer cell metabolism, glutamine metabolism, glutamylation, mechanobiology, microtubules, posttranslational modifications",
author = "St{\'e}phanie Torrino and Grasset, {Eloise M.} and Stephane Audebert and Ilyes Belhadj and Caroline Lacoux and Meagan Haynes and Sabrina Pisano and Sophie Ab{\'e}lanet and Frederic Brau and Chan, {Stephen Y.} and Bernard Mari and Oldham, {William M.} and Ewald, {Andrew J.} and Thomas Bertero",
note = "Funding Information: We thank the B. Mari team members for advice and discussions as well as F. Aguila for the artwork. The authors acknowledge the “Microscopie Imagerie C{\^o}te d'Azur” (MICA), GIS-IBISA multisites platform, and particularly its IPMC, C3M, and IRCAN (Molecular and Cellular Imaging facility PICMI) partners. This platform is supported by the GIS IBiSA , Conseil D{\'e}partemental 06 , R{\'e}gion PACA ARC , Cancer{\^o}pole PACA . Proteomic analyses were performed at the mass spectrometry facility of Marseille Proteomics supported by IBISA , Plateforme Technologique Aix-Marseille , Cancerop{\^o}le PACA , R{\'e}gion Sud Provence-Alpes-C{\^o}te d'Azur , Fonds Europ{\'e}en de D{\'e}veloppement R{\'e}gional (FEDER), and Plan Cancer . This work was supported by the French National Research Agency ( ANR-18-CE14-0025 and ANR-20-CE14-0006-02 ) and the Foundation ARC pour la recherch{\'e} sur le cancer ( PJA20191209291 to T.B.), as well as NIH grant HL128802 (to W.M.O.); NIH grants U01CA217846 and U54CA2101732 and the Breast Cancer Research Foundation grant BCRF-20-048 (to A.J.E.); NIH grants HL124021 , HL 122596 , HL 138437 , and UH2/UH3 TR002073 ; and American Heart Association grant 18EIA33900027 (to S.Y.C.). Funding Information: We thank the B. Mari team members for advice and discussions as well as F. Aguila for the artwork. The authors acknowledge the ?Microscopie Imagerie C?te d'Azur? (MICA), GIS-IBISA multisites platform, and particularly its IPMC, C3M, and IRCAN (Molecular and Cellular Imaging facility PICMI) partners. This platform is supported by the GIS IBiSA, Conseil D?partemental 06, R?gion PACA ARC, Cancer?pole PACA. Proteomic analyses were performed at the mass spectrometry facility of Marseille Proteomics supported by IBISA, Plateforme Technologique Aix-Marseille, Cancerop?le PACA, R?gion Sud Provence-Alpes-C?te d'Azur, Fonds Europ?en de D?veloppement R?gional (FEDER), and Plan Cancer. This work was supported by the French National Research Agency (ANR-18-CE14-0025 and ANR-20-CE14-0006-02) and the Foundation ARC pour la recherch? sur le cancer (PJA20191209291 to T.B.), as well as NIH grant HL128802 (to W.M.O.); NIH grants U01CA217846 and U54CA2101732 and the Breast Cancer Research Foundation grant BCRF-20-048 (to A.J.E.); NIH grants HL124021, HL 122596, HL 138437, and UH2/UH3 TR002073; and American Heart Association grant 18EIA33900027 (to S.Y.C.). S.T. and T.B. conceived and designed the experiments. S.T. E.M.G. I.B. W.M.O. and T.B. performed the majority of the experiments. W.M.O. B.M. A.J.E. and T.B. provided the experimental infrastructure. C.L. generated tubulin mutants. F.B. and S. Ab?lanet performed and analyzed STED experiments. S.P. performed and analyzed AFM experiments. S. Audebert performed and analyzed proteomic experiments. E.M.G. M.H. and A.J.E. performed and analyzed the invasion assays. S.T. S.Y.C. and T.B. wrote the manuscript. All authors participated in interpreting the results and revising the manuscript. S.Y.C. has served as a consultant for Zogenix, Aerpio, and United Therapeutics; S.Y.C. holds research grants from Actelion and Pfizer. S.Y.C. and T.B. have filed patent applications regarding the targeting of metabolism in pulmonary hypertension. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jul,
day = "6",
doi = "10.1016/j.cmet.2021.05.009",
language = "English (US)",
volume = "33",
pages = "1342--1357.e10",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "7",
}