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. 2021 Jul 6;33(7):1342-1357.e10.
doi: 10.1016/j.cmet.2021.05.009. Epub 2021 Jun 7.

Mechano-induced cell metabolism promotes microtubule glutamylation to force metastasis

Stéphanie Torrino  1 , Eloise M Grasset  2 , Stephane Audebert  3 , Ilyes Belhadj  4 , Caroline Lacoux  4 , Meagan Haynes  2 , Sabrina Pisano  5 , Sophie Abélanet  4 , Frederic Brau  4 , Stephen Y Chan  6 , Bernard Mari  4 , William M Oldham  7 , Andrew J Ewald  2 , Thomas Bertero  8
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Free article

Mechano-induced cell metabolism promotes microtubule glutamylation to force metastasis

Stéphanie Torrino et al. Cell Metab. .
Free article

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.

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Conflict of interest statement

Declaration of interests 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.

Comment in

  • Forcing MT glutamylation.
    Strzyz P. Strzyz P. Nat Rev Mol Cell Biol. 2021 Aug;22(8):509. doi: 10.1038/s41580-021-00391-5. Nat Rev Mol Cell Biol. 2021. PMID: 34135485 No abstract available.
  • Glutamylation is good for stability.
    Harjes U. Harjes U. Nat Rev Cancer. 2021 Aug;21(8):479. doi: 10.1038/s41568-021-00385-7. Nat Rev Cancer. 2021. PMID: 34172965 No abstract available.

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