Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway

Mona Hoseini Soflaee; Rushendhiran Kesavan; Umakant Sahu; Alpaslan Tasdogan; Elodie Villa; Zied Djabari; Feng Cai; Diem H. Tran; Hieu S. Vu; Eunus S. Ali; Halie Rion; Brendan P. O’Hara; Sherwin Kelekar; James Hughes Hallett; Misty Martin; Thomas P. Mathews; Peng Gao; John M. Asara; Brendan D. Manning; Issam Ben-Sahra; Gerta Hoxhaj

doi:10.1038/s41467-022-30362-z

Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway

Mona Hoseini Soflaee, Rushendhiran Kesavan, Umakant Sahu, Alpaslan Tasdogan, Elodie Villa, Zied Djabari, Feng Cai, Diem H. Tran, Hieu S. Vu, Eunus S. Ali, Halie Rion, Brendan P. O’Hara, Sherwin Kelekar, James Hughes Hallett, Misty Martin, Thomas P. Mathews, Peng Gao, John M. Asara, Brendan D. Manning, Issam Ben-SahraGerta Hoxhaj^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

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

37 Scopus citations

Abstract

Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling, and energy-dependent reactions, the impact of changes in cellular purine levels on cell physiology remains poorly understood. Here, we find that purine depletion stimulates cell migration, despite effective reduction in cell proliferation. Blocking purine synthesis triggers a shunt of glycolytic carbon into the serine synthesis pathway, which is required for the induction of cell migration upon purine depletion. The stimulation of cell migration upon a reduction in intracellular purines required one-carbon metabolism downstream of de novo serine synthesis. Decreased purine abundance and the subsequent increase in serine synthesis triggers an epithelial-mesenchymal transition (EMT) and, in cancer models, promotes metastatic colonization. Thus, reducing the available pool of intracellular purines re-routes metabolic flux from glycolysis into de novo serine synthesis, a metabolic change that stimulates a program of cell migration.

Original language	English (US)
Article number	2698
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30362-z
State	Published - Dec 2022

Funding

We thank Prof. Matthew Vander Heiden (Massachusetts Institute of Technology, Cambridge, MA) for the PKM2 wild-type and knockout MEFs and materials, Marc Morgan and Ali Shilatifard for providing us with the guide RNA targeting human P53, Min Yuan for assistance with mass spectrometry, and Vijayashree Ramesh for assistance with tail-vein injections. This research was supported by grants from the NIH: R01GM143236 (G.H.), R35-CA197459 (B.D.M.), P01-CA120964 (B.D.M. and J.A.), R00-CA194192, R01-GM135587, R01GM143334 (I.B.-S.); a Welch foundation award (I-2067-20210327(G.H.)); a TS Alliance Research Grants Program award (885252 (G.H.)), a LAM Foundation Career Development and Established Investigator Awards (LAM0127C01-18, LAM0151E01-22) (I.B.-S.); a TSC Alliance postdoctoral fellowship (SP0057487) (E.V.); and a Rothberg Courage Award from the TSC Alliance (B.D.M.). A.T. was supported by an Emmy Noether Award from the German Research Foundation (DFG, 467788900) and the Ministry of Culture and Science of the State of North Rhine-Westphalia (NRW-Nachwuchsgruppenprogramm). G.H. is recipient of a CPRIT Scholar (CPRIT; RR190087) and a V Scholar (V2021-019) awards. We thank Prof. Matthew Vander Heiden (Massachusetts Institute of Technology, Cambridge, MA) for the PKM2 wild-type and knockout MEFs and materials, Marc Morgan and Ali Shilatifard for providing us with the guide RNA targeting human P53, Min Yuan for assistance with mass spectrometry, and Vijayashree Ramesh for assistance with tail-vein injections. This research was supported by grants from the NIH: R01GM143236 (G.H.), R35-CA197459 (B.D.M.), P01-CA120964 (B.D.M. and J.A.), R00-CA194192, R01-GM135587, R01GM143334 (I.B.-S.); a Welch foundation award (I-2067-20210327(G.H.)); a TS Alliance Research Grants Program award (885252 (G.H.)), a LAM Foundation Career Development and Established Investigator Awards (LAM0127C01-18, LAM0151E01-22) (I.B.-S.); a TSC Alliance postdoctoral fellowship (SP0057487) (E.V.); and a Rothberg Courage Award from the TSC Alliance (B.D.M.). A.T. was supported by an Emmy Noether Award from the German Research Foundation (DFG, 467788900) and the Ministry of Culture and Science of the State of North Rhine-Westphalia (NRW-Nachwuchsgruppenprogramm). G.H. is recipient of a CPRIT Scholar (CPRIT; RR190087) and a V Scholar (V2021-019) awards.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

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10.1038/s41467-022-30362-z

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Soflaee, M. H., Kesavan, R., Sahu, U., Tasdogan, A., Villa, E., Djabari, Z., Cai, F., Tran, D. H., Vu, H. S., Ali, E. S., Rion, H., O’Hara, B. P., Kelekar, S., Hallett, J. H., Martin, M., Mathews, T. P., Gao, P., Asara, J. M., Manning, B. D., ... Hoxhaj, G. (2022). Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway. Nature communications, 13(1), Article 2698. https://doi.org/10.1038/s41467-022-30362-z

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abstract = "Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling, and energy-dependent reactions, the impact of changes in cellular purine levels on cell physiology remains poorly understood. Here, we find that purine depletion stimulates cell migration, despite effective reduction in cell proliferation. Blocking purine synthesis triggers a shunt of glycolytic carbon into the serine synthesis pathway, which is required for the induction of cell migration upon purine depletion. The stimulation of cell migration upon a reduction in intracellular purines required one-carbon metabolism downstream of de novo serine synthesis. Decreased purine abundance and the subsequent increase in serine synthesis triggers an epithelial-mesenchymal transition (EMT) and, in cancer models, promotes metastatic colonization. Thus, reducing the available pool of intracellular purines re-routes metabolic flux from glycolysis into de novo serine synthesis, a metabolic change that stimulates a program of cell migration.",

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Soflaee, MH, Kesavan, R, Sahu, U, Tasdogan, A, Villa, E, Djabari, Z, Cai, F, Tran, DH, Vu, HS, Ali, ES, Rion, H, O’Hara, BP, Kelekar, S, Hallett, JH, Martin, M, Mathews, TP, Gao, P, Asara, JM, Manning, BD, Ben-Sahra, I & Hoxhaj, G 2022, 'Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway', Nature communications, vol. 13, no. 1, 2698. https://doi.org/10.1038/s41467-022-30362-z

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T1 - Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway

AU - Soflaee, Mona Hoseini

AU - Kesavan, Rushendhiran

AU - Sahu, Umakant

AU - Tasdogan, Alpaslan

AU - Villa, Elodie

AU - Djabari, Zied

AU - Cai, Feng

AU - Tran, Diem H.

AU - Vu, Hieu S.

AU - Ali, Eunus S.

AU - Rion, Halie

AU - O’Hara, Brendan P.

AU - Kelekar, Sherwin

AU - Hallett, James Hughes

AU - Martin, Misty

AU - Mathews, Thomas P.

AU - Gao, Peng

AU - Asara, John M.

AU - Manning, Brendan D.

AU - Ben-Sahra, Issam

AU - Hoxhaj, Gerta

PY - 2022/12

Y1 - 2022/12

N2 - Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling, and energy-dependent reactions, the impact of changes in cellular purine levels on cell physiology remains poorly understood. Here, we find that purine depletion stimulates cell migration, despite effective reduction in cell proliferation. Blocking purine synthesis triggers a shunt of glycolytic carbon into the serine synthesis pathway, which is required for the induction of cell migration upon purine depletion. The stimulation of cell migration upon a reduction in intracellular purines required one-carbon metabolism downstream of de novo serine synthesis. Decreased purine abundance and the subsequent increase in serine synthesis triggers an epithelial-mesenchymal transition (EMT) and, in cancer models, promotes metastatic colonization. Thus, reducing the available pool of intracellular purines re-routes metabolic flux from glycolysis into de novo serine synthesis, a metabolic change that stimulates a program of cell migration.

AB - Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling, and energy-dependent reactions, the impact of changes in cellular purine levels on cell physiology remains poorly understood. Here, we find that purine depletion stimulates cell migration, despite effective reduction in cell proliferation. Blocking purine synthesis triggers a shunt of glycolytic carbon into the serine synthesis pathway, which is required for the induction of cell migration upon purine depletion. The stimulation of cell migration upon a reduction in intracellular purines required one-carbon metabolism downstream of de novo serine synthesis. Decreased purine abundance and the subsequent increase in serine synthesis triggers an epithelial-mesenchymal transition (EMT) and, in cancer models, promotes metastatic colonization. Thus, reducing the available pool of intracellular purines re-routes metabolic flux from glycolysis into de novo serine synthesis, a metabolic change that stimulates a program of cell migration.

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JO - Nature communications

JF - Nature communications

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M1 - 2698

ER -

Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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