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

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

  • Sci Adv. 2025 Mar 21;11(12):eads9182. doi: 10.1126/sciadv.ads9182.
Mariana Bustamante Eduardo 1,  Gannon Cottone 1,  Curtis W McCloskey 2,  Shiyu Liu 3,  Flavio R Palma 4,  Maria Paula Zappia 5,  Abul B M M K Islam 5,  Peng Gao 6,  Joel Setya 1,  Saya Dennis 7,  Hongyu Gao 8,  Qian Zhang 6,  Xiaoling Xuei 8,  Yuan Luo 7 9,  Jason Locasale 3,  Marcelo G Bonini 4 9,  Rama Khokha 2,  Maxim V Frolov 4 5,  Elizaveta V Benevolenskaya 4 5,  Navdeep S Chandel 9 10 11,  Seema A Khan 1 9,  Susan E Clare 1 9
Affiliations

Affiliations

  • 1 Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 2 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 3 Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
  • 4 Department of Medicine/Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 5 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.
  • 6 Robert H. Lurie Cancer Center Metabolomics Core, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 7 Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
  • 8 Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 9 Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
  • 10 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA.
  • 11 Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.
PMID: 40117373 DOI: 10.1126/sciadv.ads9182
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.

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