AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration

Eva Crosas-Molist; Vittoria Graziani; Oscar Maiques; Pahini Pandya; Joanne Monger; Remi Samain; Samantha L. George; Saba Malik; Jerrine Salise; Valle Morales; Adrien Le Guennec; R. Andrew Atkinson; Rosa M. Marti; Xavier Matias-Guiu; Guillaume Charras; Maria R. Conte; Alberto Elosegui-Artola; Mark Holt; Victoria Sanz-Moreno

doi:10.1038/s41467-023-38292-0

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration

Eva Crosas-Molist, Vittoria Graziani, Oscar Maiques, Pahini Pandya, Joanne Monger, Remi Samain, Samantha L. George, Saba Malik, Jerrine Salise, Valle Morales, Adrien Le Guennec, R. Andrew Atkinson, Rosa M. Marti, Xavier Matias-Guiu, Guillaume Charras, Maria R. Conte, Alberto Elosegui-Artola, Mark Holt, Victoria Sanz-Moreno^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

Abstract

Cell migration is crucial for cancer dissemination. We find that AMP-activated protein kinase (AMPK) controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional matrices, fast-migrating amoeboid cancer cells exert low adhesion/low traction linked to low ATP/AMP, leading to AMPK activation. In turn, AMPK plays a dual role controlling mitochondrial dynamics and cytoskeletal remodelling. High AMPK activity in low adhering migratory cells, induces mitochondrial fission, resulting in lower oxidative phosphorylation and lower mitochondrial ATP. Concurrently, AMPK inactivates Myosin Phosphatase, increasing Myosin II-dependent amoeboid migration. Reducing adhesion or mitochondrial fusion or activating AMPK induces efficient rounded-amoeboid migration. AMPK inhibition suppresses metastatic potential of amoeboid cancer cells in vivo, while a mitochondrial/AMPK-driven switch is observed in regions of human tumours where amoeboid cells are disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a mechano-metabolic sensor linking energetics and the cytoskeleton.

Original language	English
Article number	2740
Journal	Nature Communications
Volume	14
Issue number	1
Early online date	22 May 2023
DOIs	https://doi.org/10.1038/s41467-023-38292-0
Publication status	Published - Dec 2023

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Crosas-Molist, E., Graziani, V., Maiques, O., Pandya, P., Monger, J., Samain, R., George, S. L., Malik, S., Salise, J., Morales, V., Le Guennec, A., Atkinson, R. A., Marti, R. M., Matias-Guiu, X., Charras, G., Conte, M. R., Elosegui-Artola, A., Holt, M., & Sanz-Moreno, V. (2023). AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration. Nature Communications, 14(1), Article 2740. https://doi.org/10.1038/s41467-023-38292-0

@article{e2fede9d3d5f441b94d79d61deb90c80,

title = "AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration",

abstract = "Cell migration is crucial for cancer dissemination. We find that AMP-activated protein kinase (AMPK) controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional matrices, fast-migrating amoeboid cancer cells exert low adhesion/low traction linked to low ATP/AMP, leading to AMPK activation. In turn, AMPK plays a dual role controlling mitochondrial dynamics and cytoskeletal remodelling. High AMPK activity in low adhering migratory cells, induces mitochondrial fission, resulting in lower oxidative phosphorylation and lower mitochondrial ATP. Concurrently, AMPK inactivates Myosin Phosphatase, increasing Myosin II-dependent amoeboid migration. Reducing adhesion or mitochondrial fusion or activating AMPK induces efficient rounded-amoeboid migration. AMPK inhibition suppresses metastatic potential of amoeboid cancer cells in vivo, while a mitochondrial/AMPK-driven switch is observed in regions of human tumours where amoeboid cells are disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a mechano-metabolic sensor linking energetics and the cytoskeleton.",

author = "Eva Crosas-Molist and Vittoria Graziani and Oscar Maiques and Pahini Pandya and Joanne Monger and Remi Samain and George, {Samantha L.} and Saba Malik and Jerrine Salise and Valle Morales and {Le Guennec}, Adrien and Atkinson, {R. Andrew} and Marti, {Rosa M.} and Xavier Matias-Guiu and Guillaume Charras and Conte, {Maria R.} and Alberto Elosegui-Artola and Mark Holt and Victoria Sanz-Moreno",

note = "Funding Information: The work was supported by Cancer Research UK (CRUK) C33043/A12065 and C33043/A24478 (V.S.M., E.C.M., O.M., P.P.); Barts Charity (V.S.M., V.G., J.M., R.S., S.L.G.); Royal Society RG110591 (V.S.M.); Fundaci{\'o}n Ram{\'o}n Areces (E.C.M.); World Wide Cancer Research 22-0329 (V.S.M., V.G.); ISCIII/FEDER “Una manera de hacer Europa” FIS-PI1500711 and PI18/00573 (R.M.M.); CIBERONC CB16/12/0023 (R.M.M. and X.M.G.), and from the European Research Council (E.R.C.) under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (StG- 851055 to A.E.A.). A.E.A. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2214), the UK Medical Research Council (CC2214), and the Wellcome Trust (CC2214). We thank the Centre for Biomolecular Spectroscopy for access to biophysical infrastructure. The Centre was funded by the Welcome and British Heart Foundation grants to MRC (ref. 202767/Z/16/Z and IG/16/2/32273 respectively). We acknowledge the metabolic flux analysis facility of the Barts School of Medicine and Dentistry created with the support of the Barts and the London Charity - grant number MGU0401. We thank Kairbaan Hodivala-Dilke, Jeremy Carlton and Ver{\'o}nica Torrano for helpful discussions and Fredrik Wallberg for technical advice. Illustrations were created with BioRender.com. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-38292-0",

language = "English",

volume = "14",

journal = "Nature Communications",

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Crosas-Molist, E, Graziani, V, Maiques, O, Pandya, P, Monger, J, Samain, R, George, SL, Malik, S, Salise, J, Morales, V, Le Guennec, A , Atkinson, RA, Marti, RM, Matias-Guiu, X, Charras, G, Conte, MR, Elosegui-Artola, A, Holt, M & Sanz-Moreno, V 2023, 'AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration', Nature Communications, vol. 14, no. 1, 2740. https://doi.org/10.1038/s41467-023-38292-0

TY - JOUR

T1 - AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration

AU - Crosas-Molist, Eva

AU - Graziani, Vittoria

AU - Maiques, Oscar

AU - Pandya, Pahini

AU - Monger, Joanne

AU - Samain, Remi

AU - George, Samantha L.

AU - Malik, Saba

AU - Salise, Jerrine

AU - Morales, Valle

AU - Le Guennec, Adrien

AU - Atkinson, R. Andrew

AU - Marti, Rosa M.

AU - Matias-Guiu, Xavier

AU - Charras, Guillaume

AU - Conte, Maria R.

AU - Elosegui-Artola, Alberto

AU - Holt, Mark

AU - Sanz-Moreno, Victoria

N1 - Funding Information: The work was supported by Cancer Research UK (CRUK) C33043/A12065 and C33043/A24478 (V.S.M., E.C.M., O.M., P.P.); Barts Charity (V.S.M., V.G., J.M., R.S., S.L.G.); Royal Society RG110591 (V.S.M.); Fundación Ramón Areces (E.C.M.); World Wide Cancer Research 22-0329 (V.S.M., V.G.); ISCIII/FEDER “Una manera de hacer Europa” FIS-PI1500711 and PI18/00573 (R.M.M.); CIBERONC CB16/12/0023 (R.M.M. and X.M.G.), and from the European Research Council (E.R.C.) under the European Union’s Horizon 2020 research and innovation programme (StG- 851055 to A.E.A.). A.E.A. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2214), the UK Medical Research Council (CC2214), and the Wellcome Trust (CC2214). We thank the Centre for Biomolecular Spectroscopy for access to biophysical infrastructure. The Centre was funded by the Welcome and British Heart Foundation grants to MRC (ref. 202767/Z/16/Z and IG/16/2/32273 respectively). We acknowledge the metabolic flux analysis facility of the Barts School of Medicine and Dentistry created with the support of the Barts and the London Charity - grant number MGU0401. We thank Kairbaan Hodivala-Dilke, Jeremy Carlton and Verónica Torrano for helpful discussions and Fredrik Wallberg for technical advice. Illustrations were created with BioRender.com. Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - Cell migration is crucial for cancer dissemination. We find that AMP-activated protein kinase (AMPK) controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional matrices, fast-migrating amoeboid cancer cells exert low adhesion/low traction linked to low ATP/AMP, leading to AMPK activation. In turn, AMPK plays a dual role controlling mitochondrial dynamics and cytoskeletal remodelling. High AMPK activity in low adhering migratory cells, induces mitochondrial fission, resulting in lower oxidative phosphorylation and lower mitochondrial ATP. Concurrently, AMPK inactivates Myosin Phosphatase, increasing Myosin II-dependent amoeboid migration. Reducing adhesion or mitochondrial fusion or activating AMPK induces efficient rounded-amoeboid migration. AMPK inhibition suppresses metastatic potential of amoeboid cancer cells in vivo, while a mitochondrial/AMPK-driven switch is observed in regions of human tumours where amoeboid cells are disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a mechano-metabolic sensor linking energetics and the cytoskeleton.

AB - Cell migration is crucial for cancer dissemination. We find that AMP-activated protein kinase (AMPK) controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional matrices, fast-migrating amoeboid cancer cells exert low adhesion/low traction linked to low ATP/AMP, leading to AMPK activation. In turn, AMPK plays a dual role controlling mitochondrial dynamics and cytoskeletal remodelling. High AMPK activity in low adhering migratory cells, induces mitochondrial fission, resulting in lower oxidative phosphorylation and lower mitochondrial ATP. Concurrently, AMPK inactivates Myosin Phosphatase, increasing Myosin II-dependent amoeboid migration. Reducing adhesion or mitochondrial fusion or activating AMPK induces efficient rounded-amoeboid migration. AMPK inhibition suppresses metastatic potential of amoeboid cancer cells in vivo, while a mitochondrial/AMPK-driven switch is observed in regions of human tumours where amoeboid cells are disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a mechano-metabolic sensor linking energetics and the cytoskeleton.

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U2 - 10.1038/s41467-023-38292-0

DO - 10.1038/s41467-023-38292-0

M3 - Article

C2 - 37217519

AN - SCOPUS:85159806924

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2740

ER -

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration

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