期刊
CELL METABOLISM
卷 33, 期 7, 页码 1342-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2021.05.009
关键词
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资金
- IBISA
- Plateforme Technologique AixMarseille
- Canceropo le PACA
- Region Sud Provence Alpes Cote d'Azur
- Fonds Europeen de Developpement Regional (FEDER)
- French National Research Agency [ANR-18-CE14-0025, ANR-20-CE14-0006-02]
- Foundation ARC pour la recherche sur le cancer [PJA20191209291]
- NIH [HL128802, U01CA217846, U54CA2101732, HL124021, HL122596, HL138437, UH2/UH3 TR002073]
- Breast Cancer Research Foundation [BCRF-20-048]
- American Heart Association [18EIA33900027]
- Plan Cancer
- GIS IBiSA
- Conseil Departemental 06
- Region PACA ARC
- Cancero pole PACA
- Agence Nationale de la Recherche (ANR) [ANR-18-CE14-0025, ANR-20-CE14-0006] Funding Source: Agence Nationale de la Recherche (ANR)
In this study, it was found that breast cancer cells respond to mechanical signals by rewiring glutamine metabolism to promote microtubule glutamylation and enhance microtubule stability, thereby promoting cell invasion. Inhibition of glutamine metabolism affects microtubule stability, while reducing microtubule glutamylation weakens cancer aggressiveness.
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.
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