A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells

Mariana Bustamante Eduardo; Gannon Cottone; Curtis W. McCloskey; Shiyu Liu; Flavio R. Palma; Maria Paula Zappia; Abul B.M.M.K. Islam; Peng Gao; Joel Setya; Saya Dennis; Hongyu Gao; Qian Zhang; Xiaoling Xuei; Yuan Luo; Jason Locasale; Marcelo G. Bonini; Rama Khokha; Maxim V. Frolov; Elizaveta V. Benevolenskaya; Navdeep S. Chandel; Seema A. Khan; Susan E. Clare

doi:10.1126/sciadv.ads9182

A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells

Mariana Bustamante Eduardo, Gannon Cottone, Curtis W. McCloskey, Shiyu Liu, Flavio R. Palma, Maria Paula Zappia, Abul B.M.M.K. Islam, Peng Gao, Joel Setya, Saya Dennis, Hongyu Gao, Qian Zhang, Xiaoling Xuei, Yuan Luo, Jason Locasale, Marcelo G. Bonini, Rama Khokha, Maxim V. Frolov, Elizaveta V. Benevolenskaya, Navdeep S. ChandelSeema A. Khan, Susan E. Clare^*

^*Corresponding author for this work

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

Abstract

Lipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor–negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer.

Original language	English (US)
Article number	eads9182
Journal	Science Advances
Volume	11
Issue number	12
DOIs	https://doi.org/10.1126/sciadv.ads9182
State	Published - Mar 21 2025

Funding

We thank Robert H. Lurie Comprehensive Cancer Center Metabolomics Core for Metabolomics Services. We would like to thank the Center for Medical Genomics at the Indiana University School of Medicine for CUT&RUN sequencing. We thank the UIC single-cell sequencing pilot for SCRNA-seq. We acknowledge P. Glazer (Yale University) for supplying us with the homologous recombination reporter plasmid. We thank the University of Minnesota Genotyping services for conducting the MethylationEpic array. We are grateful to our many laboratory colleagues for constructive feedback. This research was supported by the 2023 AACR-Pfizer Breast Cancer Research Fellowship (grant number 23-40-49-BUST to M.B.E.), the Breast Cancer Research Foundation, Avon Foundation and Bluhm Family Foundation Foundation (to S.A.K.), and the National Cancer Institute R21 CA282428 (to E.V.B.).

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Eduardo, M. B., Cottone, G., McCloskey, C. W., Liu, S., Palma, F. R., Zappia, M. P., Islam, A. B. M. M. K., Gao, P., Setya, J., Dennis, S., Gao, H., Zhang, Q., Xuei, X., Luo, Y., Locasale, J., Bonini, M. G., Khokha, R., Frolov, M. V., Benevolenskaya, E. V., ... Clare, S. E. (2025). A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells. Science Advances, 11(12), Article eads9182. https://doi.org/10.1126/sciadv.ads9182

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title = "A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells",

abstract = "Lipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor–negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer.",

author = "Eduardo, {Mariana Bustamante} and Gannon Cottone and McCloskey, {Curtis W.} and Shiyu Liu and Palma, {Flavio R.} and Zappia, {Maria Paula} and Islam, {Abul B.M.M.K.} and Peng Gao and Joel Setya and Saya Dennis and Hongyu Gao and Qian Zhang and Xiaoling Xuei and Yuan Luo and Jason Locasale and Bonini, {Marcelo G.} and Rama Khokha and Frolov, {Maxim V.} and Benevolenskaya, {Elizaveta V.} and Chandel, {Navdeep S.} and Khan, {Seema A.} and Clare, {Susan E.}",

note = "Publisher Copyright: {\textcopyright} 2025 the Authors, some rights reserved;",

year = "2025",

month = mar,

day = "21",

doi = "10.1126/sciadv.ads9182",

language = "English (US)",

volume = "11",

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Eduardo, MB, Cottone, G, McCloskey, CW, Liu, S, Palma, FR, Zappia, MP, Islam, ABMMK, Gao, P, Setya, J, Dennis, S, Gao, H, Zhang, Q, Xuei, X, Luo, Y, Locasale, J, Bonini, MG, Khokha, R, Frolov, MV, Benevolenskaya, EV, Chandel, NS , Khan, SA & Clare, SE 2025, 'A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells', Science Advances, vol. 11, no. 12, eads9182. https://doi.org/10.1126/sciadv.ads9182

TY - JOUR

T1 - A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells

AU - Eduardo, Mariana Bustamante

AU - Cottone, Gannon

AU - McCloskey, Curtis W.

AU - Liu, Shiyu

AU - Palma, Flavio R.

AU - Zappia, Maria Paula

AU - Islam, Abul B.M.M.K.

AU - Gao, Peng

AU - Setya, Joel

AU - Dennis, Saya

AU - Gao, Hongyu

AU - Zhang, Qian

AU - Xuei, Xiaoling

AU - Luo, Yuan

AU - Locasale, Jason

AU - Bonini, Marcelo G.

AU - Khokha, Rama

AU - Frolov, Maxim V.

AU - Benevolenskaya, Elizaveta V.

AU - Chandel, Navdeep S.

AU - Khan, Seema A.

AU - Clare, Susan E.

PY - 2025/3/21

Y1 - 2025/3/21

N2 - Lipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor–negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer.

AB - Lipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor–negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer.

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U2 - 10.1126/sciadv.ads9182

DO - 10.1126/sciadv.ads9182

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SN - 2375-2548

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JO - Science Advances

JF - Science Advances

IS - 12

M1 - eads9182

ER -

A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells

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