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. 2025 Mar 21;11(12):eads9182.
doi: 10.1126/sciadv.ads9182. Epub 2025 Mar 21.

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

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

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

Mariana Bustamante Eduardo et al. Sci Adv. .

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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Figures

Fig. 1.
Fig. 1.. Metabolic shift.
(A) Metabolism of OA results in a metabolic shift toward the de novo serine pathway. (B) Fractional abundance of SAM isotopologues. **P < 0.01, ****P < 0.0001 [two-way analysis of variance (ANOVA) with Tukey test, n = 3, mean with SD]. Four hours of labeling. Right: Schematic of derivation and contribution of carbon atoms in SAM synthesis. (C) 13C metabolic flux calculations. Cancer index was calculated as the lactate ratio. (D) Measurement of serine, SAM, betaine+, GSH, 2-HG, NADH, and αKG after 15- and 30-min (E) exposure to PBS (vehicle), OA, PBS plus DMSO (vehicle), and OA plus CBR-5884. *P < 0.05, **P < 0.01, ***P < 0.001 (two-way ANOVA with Tukey test, n = 3, mean with SEM).
Fig. 2.
Fig. 2.. Epigenetic reprogramming.
(A) Increases in 2-HG and SAM lead to epigenomic reprogramming. (B) Pie chart depicting the distribution of OA-associated H3K4me3 peaks (FDR < 0.01) at OA-modulated genes (FDR < 0.01). (C) Table depicting relevant transcription factor (TF) motifs identified with HOMER in increased H3K4me3 peaks and their associated activity. (D) Histograms showing H3K4me3 occupancy at NGFR, NGF, PARM1, and MDK in vehicle (gray tracks) and OA (green tracks). The peaks are visualized with the WashU Epigenome Browser. The bottom panel shows boxplots of RNA expression reads per kilobase of transcript per million mapped reads (RPKM) values. ****P < 0.0001. (E) Gene Ontology (GO) Biological Process 2021 and WikiPathway 2021 classifications for genes overexpressed upon OA treatment and associated with increased H3K4me3 peaks. (F) Boxplots showing the expression of OA-induced genes upon OA, OA plus CBR-5884, and OA plus Piribedil measured by qPCR. +Gene with enriched H3K4me3 peak upon OA. (G) Boxplots showing the expression of OA-induced neural-related genes with enriched H3K4me3 peaks. *P < 0.05, **P < 0.01 (multiple unpaired t test, mean with SEM).
Fig. 3.
Fig. 3.. Antioxidant defenses.
(A) Cells deploy antioxidant defenses to control the concentration of ROS. (B) Quantification of mito-roGFP2-Orp1 and nls-roGFP2-Orp1 monitoring mitochondrial and nuclear redox state in MCF-10A cells, respectively. Ratio of emission at 405 and 488 nm obtained as a response of OA exposure. ****P < 0.0001 (ordinary one-way ANOVA with Tukey test, mean with SD). (C) Representative pictures of mito-roGFP2-Orp1 and nls-roGFP2-Orp1 monitoring mitochondrial and nuclear redox state in MCF-10A cells. Scale bar, 200 μm. (D) Comet tail moment for control MCF-10A (vehicle), doxycycline (DOX)-induced PHGDH, MCF-10A in the presence of OA ± PHGDH inhibitors (CBR-5884 or NTC-503), or NTC-503 inactive control and 2-HG. (E) Quantification of (D). **P < 0.01, ****P < 0.0001 (two-way ANOVA with Tukey test, mean with SEM).
Fig. 4.
Fig. 4.. Single-cell landscape of vehicle- and OA-treated tissue-derived breast microstructures.
Uniform Manifold Approximation and Projection (UMAP) plot of 36,904 cells identified a total of 25 different cell clusters. Cell subtypes defined by Reed et al. (65). Table shows cell subtype proportions.
Fig. 5.
Fig. 5.. Feature plots of vehicle- and OA-treated cells from tissue-derived breast microstructures.
(A) Metabolism of OA results in a metabolic shift toward the de novo serine pathway. (B) Feature plot of cells that are labeled according to ATF3, PHGDH, and PSAT1 de novo serine-related genes. (C) Increases in 2-HG and SAM lead to epigenomic reprogramming. (D) Feature plot of cells that are labeled according to neural-related gene NGFR, NGF, and PARM1 transcription, which are genes controlled by H3K4me3.
Fig. 6.
Fig. 6.. scRNA-seq analysis.
(A) Venn diagram depicting genes up-regulated by OA in MCF-10A, genes with increased H3K4me3 peaks upon OA in MCF-10A, and up-regulated genes by OA in breast microstructures measured by scRNA-seq. (B) Feature plot of cells that are labeled according to neuronal system gene set. (C) Violin plot shows ssGSEA score of Reactome neuronal system in BSL1, HS1, and LP3 subtypes. (D) Circle plot of a selection of intercellular communication signaling network in OA and vehicle.
Fig. 7.
Fig. 7.. Metabolic systems affected by OA.
Specific reactions in BSL1 (top), LP3 (middle), and HS1 (bottom) of glycine, serine, alanine, and threonine metabolism (reactions of the de novo serine pathway in green); ROS detoxification (catalase in green); glutathione metabolism (glutathione in green); and tyrosine metabolism (neurotransmitter-related reactions in green). Complete list of reactions in tables S8 to S10.
Fig. 8.
Fig. 8.. OA induced shift of metabolism away from glycolysis to the SOG/methionine cycle.
(1) Metabolic shift leads to (2) increased 2-HG, which impairs DNA repair and contribute to epigenetic fostered plasticity; (3) increased SAM, which is responsible for epigenetic induced plasticity; and (4) increased glutathione (GSH) to counter the ROS and thus enabling survival of a subset of cells and contributing to DNA damage. SHMT1, serine hydroxymethyltransferase 1; TS, thymidylate synthase; DHF, dihydrofolic acid; DHFR, dihydrofolate reductase; MS, methionine synthase; MTHFS, methenyltetrahydrofolate synthetase; THF, tetrahydrofolate; MET, methionine; HCyst, homocysteine. Sections of this picture are shown in the previous figures.
See this image and copyright information in PMC

References

    1. Lima S. M., Kehm R. D., Terry M. B., Global breast cancer incidence and mortality trends by region, age-groups, and fertility patterns. EClinicalMedicine 38, 100985 (2021). - PMC - PubMed
    1. Global Burden of Disease 2019 Cancer Collaboration , Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: A systematic analysis for the global burden of disease study 2019. JAMA Oncol. 8, 420–444 (2022). - PMC - PubMed
    1. Sporn M. B., Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res. 36, 2699–2702 (1976). - PubMed
    1. Yang X. R., Chang-Claude J., Goode E. L., Couch F. J., Nevanlinna H., Milne R. L., Gaudet M., Schmidt M. K., Broeks A., Cox A., Fasching P. A., Hein R., Spurdle A. B., Blows F., Driver K., Flesch-Janys D., Heinz J., Sinn P., Vrieling A., Heikkinen T., Aittomäki K., Heikkilä P., Blomqvist C., Lissowska J., Peplonska B., Chanock S., Figueroa J., Brinton L., Hall P., Czene K., Humphreys K., Darabi H., Liu J., 't Veer L. J., Leeuwen F. E., Andrulis I. L., Glendon G., Knight J. A., Mulligan A. M., O'Malley F. P., Weerasooriya N., John E. M., Beckmann M. W., Hartmann A., Weihbrecht S. B., Wachter D. L., Jud S. M., Loehberg C. R., Baglietto L., English D. R., Giles G. G., McLean C. A., Severi G., Lambrechts D., Vandorpe T., Weltens C., Paridaens R., Smeets A., Neven P., Wildiers H., Wang X., Olson J. E., Cafourek V., Fredericksen Z., Kosel M., Vachon C., Cramp H. E., Connley D., Cross S. S., Balasubramanian S. P., Reed M. W., Dörk T., Bremer M., Meyer A., Karstens J. H., Ay A., Park-Simon T. W., Hillemanns P., Arias Pérez J. I., Menéndez Rodríguez P., Zamora P., Benítez J., Ko Y. D., Fischer H. P., Hamann U., Pesch B., Brüning T., Justenhoven C., Brauch H., Eccles D. M., Tapper W. J., Gerty S. M., Sawyer E. J., Tomlinson I. P., Jones A., Kerin M., Miller N., McInerney N., Anton-Culver H., Ziogas A., Shen C. Y., Hsiung C. N., Wu P. E., Yang S. L., Yu J. C., Chen S. T., Hsu G. C., Haiman C. A., Henderson B. E., Marchand L., Kolonel L. N., Lindblom A., Margolin S., Jakubowska A., Lubiński J., Huzarski T., Byrski T., Górski B., Gronwald J., Hooning M. J., Hollestelle A., Ouweland A. M., Jager A., Kriege M., Tilanus-Linthorst M. M., Collée M., Wang-Gohrke S., Pylkäs K., Jukkola-Vuorinen A., Mononen K., Grip M., Hirvikoski P., Winqvist R., Mannermaa A., Kosma V. M., Kauppinen J., Kataja V., Auvinen P., Soini Y., Sironen R., Bojesen S. E., Ørsted D. D., Kaur-Knudsen D., Flyger H., Nordestgaard B. G., Holland H., Chenevix-Trench G., Manoukian S., Barile M., Radice P., Hankinson S. E., Hunter D. J., Tamimi R., Sangrajrang S., Brennan P., McKay J., Odefrey F., Gaborieau V., Devilee P., Huijts P. E., Tollenaar R. A., Seynaeve C., Dite G. S., Apicella C., Hopper J. L., Hammet F., Tsimiklis H., Smith L. D., Southey M. C., Humphreys M. K., Easton D., Pharoah P., Sherman M. E., Garcia-Closas M., Associations of breast cancer risk factors with tumor subtypes: A pooled analysis from the Breast Cancer Association Consortium studies. J. Natl. Cancer Inst. 103, 250–263 (2011). - PMC - PubMed
    1. Milne R. L., Kuchenbaecker K. B., Michailidou K., Beesley J., Kar S., Lindström S., Hui S., Lemaçon A., Soucy P., Dennis J., Jiang X., Rostamianfar A., Finucane H., Bolla M. K., McGuffog L., Wang Q., Aalfs C. M., Adams M., Adlard J., Agata S., Ahmed S., Ahsan H., Aittomäki K., Al-Ejeh F., Allen J., Ambrosone C. B., Amos C. I., Andrulis I. L., Anton-Culver H., Antonenkova N. N., Arndt V., Arnold N., Aronson K. J., Auber B., Auer P. L., Ausems M., Azzollini J., Bacot F., Balmaña J., Barile M., Barjhoux L., Barkardottir R. B., Barrdahl M., Barnes D., Barrowdale D., Baynes C., Beckmann M. W., Benitez J., Bermisheva M., Bernstein L., Bignon Y. J., Blazer K. R., Blok M. J., Blomqvist C., Blot W., Bobolis K., Boeckx B., Bogdanova N. V., Bojesen A., Bojesen S. E., Bonanni B., Børresen-Dale A. L., Bozsik A., Bradbury A. R., Brand J. S., Brauch H., Brenner H., Paillerets B. B.-d., Brewer C., Brinton L., Broberg P., Brooks-Wilson A., Brunet J., Brüning T., Burwinkel B., Buys S. S., Byun J., Cai Q., Caldés T., Caligo M. A., Campbell I., Canzian F., Caron O., Carracedo A., Carter B. D., Castelao J. E., Castera L., Caux-Moncoutier V., Chan S. B., Chang-Claude J., Chanock S. J., Chen X., Cheng T. D., Chiquette J., Christiansen H., Claes K. B. M., Clarke C. L., Conner T., Conroy D. M., Cook J., Cordina-Duverger E., Cornelissen S., Coupier I., Cox A., Cox D. G., Cross S. S., Cuk K., Cunningham J. M., Czene K., Daly M. B., Damiola F., Darabi H., Davidson R., De Leeneer K., Devilee P., Dicks E., Diez O., Ding Y. C., Ditsch N., Doheny K. F., Domchek S. M., Dorfling C. M., Dörk T., Dos-Santos-Silva I., Dubois S., Dugué P. A., Dumont M., Dunning A. M., Durcan L., Dwek M., Dworniczak B., Eccles D., Eeles R., Ehrencrona H., Eilber U., Ejlertsen B., Ekici A. B., Eliassen A. H., Engel C., Eriksson M., Fachal L., Faivre L., Fasching P. A., Faust U., Figueroa J., Flesch-Janys D., Fletcher O., Flyger H., Foulkes W. D., Friedman E., Fritschi L., Frost D., Gabrielson M., Gaddam P., Gammon M. D., Ganz P. A., Gapstur S. M., Garber J., Garcia-Barberan V., García-Sáenz J. A., Gaudet M. M., Gauthier-Villars M., Gehrig A., Georgoulias V., Gerdes A. M., Giles G. G., Glendon G., Godwin A. K., Goldberg M. S., Goldgar D. E., González-Neira A., Goodfellow P., Greene M. H., Alnæs G. I. G., Grip M., Gronwald J., Grundy A., Gschwantler-Kaulich D., Guénel P., Guo Q., Haeberle L., Hahnen E., Haiman C. A., Håkansson N., Hallberg E., Hamann U., Hamel N., Hankinson S., Hansen T. V. O., Harrington P., Hart S. N., Hartikainen J. M., Healey C. S., Hein A., Helbig S., Henderson A., Heyworth J., Hicks B., Hillemanns P., Hodgson S., Hogervorst F. B., Hollestelle A., Hooning M. J., Hoover B., Hopper J. L., Hu C., Huang G., Hulick P. J., Humphreys K., Hunter D. J., Imyanitov E. N., Isaacs C., Iwasaki M., Izatt L., Jakubowska A., James P., Janavicius R., Janni W., Jensen U. B., John E. M., Johnson N., Jones K., Jones M., Jukkola-Vuorinen A., Kaaks R., Kabisch M., Kaczmarek K., Kang D., Kast K., Keeman R., Kerin M. J., Kets C. M., Keupers M., Khan S., Khusnutdinova E., Kiiski J. I., Kim S. W., Knight J. A., Konstantopoulou I., Kosma V. M., Kristensen V. N., Kruse T. A., Kwong A., Lænkholm A. V., Laitman Y., Lalloo F., Lambrechts D., Landsman K., Lasset C., Lazaro C., Le Marchand L., Lecarpentier J., Lee A., Lee E., Lee J. W., Lee M. H., Lejbkowicz F., Lesueur F., Li J., Lilyquist J., Lincoln A., Lindblom A., Lissowska J., Lo W. Y., Loibl S., Long J., Loud J. T., Lubinski J., Luccarini C., Lush M., MacInnis R. J., Maishman T., Makalic E., Kostovska I. M., Malone K. E., Manoukian S., Manson J. E., Margolin S., Martens J. W. M., Martinez M. E., Matsuo K., Mavroudis D., Mazoyer S., McLean C., Meijers-Heijboer H., Menéndez P., Meyer J., Miao H., Miller A., Miller N., Mitchell G., Montagna M., Muir K., Mulligan A. M., Mulot C., Nadesan S., Nathanson K. L., Neuhausen S. L., Nevanlinna H., Nevelsteen I., Niederacher D., Nielsen S. F., Nordestgaard B. G., Norman A., Nussbaum R. L., Olah E., Olopade O. I., Olson J. E., Olswold C., Ong K. R., Oosterwijk J. C., Orr N., Osorio A., Pankratz V. S., Papi L., Park-Simon T. W., Paulsson-Karlsson Y., Lloyd R., Pedersen I. S., Peissel B., Peixoto A., Perez J. I. A., Peterlongo P., Peto J., Pfeiler G., Phelan C. M., Pinchev M., Plaseska-Karanfilska D., Poppe B., Porteous M. E., Prentice R., Presneau N., Prokofieva D., Pugh E., Pujana M. A., Pylkäs K., Rack B., Radice P., Rahman N., Rantala J., Rappaport-Fuerhauser C., Rennert G., Rennert H. S., Rhenius V., Rhiem K., Richardson A., Rodriguez G. C., Romero A., Romm J., Rookus M. A., Rudolph A., Ruediger T., Saloustros E., Sanders J., Sandler D. P., Sangrajrang S., Sawyer E. J., Schmidt D. F., Schoemaker M. J., Schumacher F., Schürmann P., Schwentner L., Scott C., Scott R. J., Seal S., Senter L., Seynaeve C., Shah M., Sharma P., Shen C. Y., Sheng X., Shimelis H., Shrubsole M. J., Shu X. O., Side L. E., Singer C. F., Sohn C., Southey M. C., Spinelli J. J., Spurdle A. B., Stegmaier C., Stoppa-Lyonnet D., Sukiennicki G., Surowy H., Sutter C., Swerdlow A., Szabo C. I., Tamimi R. M., Tan Y. Y., Taylor J. A., Tejada M. I., Tengström M., Teo S. H., Terry M. B., Tessier D. C., Teulé A., Thöne K., Thull D. L., Tibiletti M. G., Tihomirova L., Tischkowitz M., Toland A. E., Tollenaar R., Tomlinson I., Tong L., Torres D., Tranchant M., Truong T., Tucker K., Tung N., Tyrer J., Ulmer H. U., Vachon C., van Asperen C. J., Van Den Berg D., van den Ouweland A. M. W., van Rensburg E. J., Varesco L., Varon-Mateeva R., Vega A., Viel A., Vijai J., Vincent D., Vollenweider J., Walker L., Wang Z., Wang-Gohrke S., Wappenschmidt B., Weinberg C. R., Weitzel J. N., Wendt C., Wesseling J., Whittemore A. S., Wijnen J. T., Willett W., Winqvist R., Wolk A., Wu A. H., Xia L., Yang X. R., Yannoukakos D., Zaffaroni D., Zheng W., Zhu B., Ziogas A., Ziv E., Zorn K. K., Gago-Dominguez M., Mannermaa A., Olsson H., Teixeira M. R., Stone J., Offit K., Ottini L., Park S. K., Thomassen M., Hall P., Meindl A., Schmutzler R. K., Droit A., Bader G. D., Pharoah P. D. P., Couch F. J., Easton D. F., Kraft P., Chenevix-Trench G., García-Closas M., Schmidt M. K., Antoniou A. C., Simard J., Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat. Genet. 49, 1767–1778 (2017). - PMC - PubMed