Transcription factor NKX2-1 drives serine and glycine synthesis addiction in cancer.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
16
01
2023
accepted:
21
02
2023
revised:
10
02
2023
medline:
1
5
2023
pubmed:
19
3
2023
entrez:
18
3
2023
Statut:
ppublish
Résumé
One-third of cancers activate endogenous synthesis of serine/glycine, and can become addicted to this pathway to sustain proliferation and survival. Mechanisms driving this metabolic rewiring remain largely unknown. NKX2-1 overexpressing and NKX2-1 knockdown/knockout T-cell leukaemia and lung cancer cell line models were established to study metabolic rewiring using ChIP-qPCR, immunoblotting, mass spectrometry, and proliferation and invasion assays. Findings and therapeutic relevance were validated in mouse models and confirmed in patient datasets. Exploring T-cell leukaemia, lung cancer and neuroendocrine prostate cancer patient datasets highlighted the transcription factor NKX2-1 as putative driver of serine/glycine metabolism. We demonstrate that transcription factor NKX2-1 binds and transcriptionally upregulates serine/glycine synthesis enzyme genes, enabling NKX2-1 expressing cells to proliferate and invade in serine/glycine-depleted conditions. NKX2-1 driven serine/glycine synthesis generates nucleotides and redox molecules, and is associated with an altered cellular lipidome and methylome. Accordingly, NKX2-1 tumour-bearing mice display enhanced tumour aggressiveness associated with systemic metabolic rewiring. Therapeutically, NKX2-1-expressing cancer cells are more sensitive to serine/glycine conversion inhibition by repurposed anti-depressant sertraline, and to etoposide chemotherapy. Collectively, we identify NKX2-1 as a novel transcriptional regulator of serine/glycine synthesis addiction across cancers, revealing a therapeutic vulnerability of NKX2-1-driven cancers. Transcription factor NKX2-1 fuels cancer cell proliferation and survival by hyperactivating serine/glycine synthesis, highlighting this pathway as a novel therapeutic target in NKX2-1-positive cancers.
Sections du résumé
BACKGROUND
One-third of cancers activate endogenous synthesis of serine/glycine, and can become addicted to this pathway to sustain proliferation and survival. Mechanisms driving this metabolic rewiring remain largely unknown.
METHODS
NKX2-1 overexpressing and NKX2-1 knockdown/knockout T-cell leukaemia and lung cancer cell line models were established to study metabolic rewiring using ChIP-qPCR, immunoblotting, mass spectrometry, and proliferation and invasion assays. Findings and therapeutic relevance were validated in mouse models and confirmed in patient datasets.
RESULTS
Exploring T-cell leukaemia, lung cancer and neuroendocrine prostate cancer patient datasets highlighted the transcription factor NKX2-1 as putative driver of serine/glycine metabolism. We demonstrate that transcription factor NKX2-1 binds and transcriptionally upregulates serine/glycine synthesis enzyme genes, enabling NKX2-1 expressing cells to proliferate and invade in serine/glycine-depleted conditions. NKX2-1 driven serine/glycine synthesis generates nucleotides and redox molecules, and is associated with an altered cellular lipidome and methylome. Accordingly, NKX2-1 tumour-bearing mice display enhanced tumour aggressiveness associated with systemic metabolic rewiring. Therapeutically, NKX2-1-expressing cancer cells are more sensitive to serine/glycine conversion inhibition by repurposed anti-depressant sertraline, and to etoposide chemotherapy.
CONCLUSION
Collectively, we identify NKX2-1 as a novel transcriptional regulator of serine/glycine synthesis addiction across cancers, revealing a therapeutic vulnerability of NKX2-1-driven cancers. Transcription factor NKX2-1 fuels cancer cell proliferation and survival by hyperactivating serine/glycine synthesis, highlighting this pathway as a novel therapeutic target in NKX2-1-positive cancers.
Identifiants
pubmed: 36932191
doi: 10.1038/s41416-023-02216-y
pii: 10.1038/s41416-023-02216-y
pmc: PMC10147615
doi:
Substances chimiques
Glycine
TE7660XO1C
NKX2-1 protein, human
0
Nkx2-1 protein, mouse
0
Serine
452VLY9402
Thyroid Nuclear Factor 1
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1862-1878Informations de copyright
© 2023. The Author(s).
Références
Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.
pubmed: 26771115
pmcid: 4715268
doi: 10.1016/j.cmet.2015.12.006
Geeraerts SL, Heylen E, De Keersmaecker K, Kampen KR. The ins and outs of serine and glycine metabolism in cancer. Nat Metab. 2021;3:131–41.
Mattaini KR, Sullivan MR, Vander, Heiden MG. The importance of serine metabolism in cancer. J Cell Biol. 2016;214:249–57.
pubmed: 27458133
pmcid: 4970329
doi: 10.1083/jcb.201604085
Yang M, Vousden KH. Serine and one-carbon metabolism in cancer. Nat Rev Cancer. 2016;16:650–62.
pubmed: 27634448
doi: 10.1038/nrc.2016.81
Geeraerts S, Kampen K, Rinaldi G, Gupta P, Planque M, de Cremer K, et al. Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis addicted breast tumor growth. Mol Cancer Ther. 2020;20:50–63.
Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 2011;43:869–74.
pubmed: 21804546
pmcid: 3677549
doi: 10.1038/ng.890
Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 2011;476:346–50.
pubmed: 21760589
pmcid: 3353325
doi: 10.1038/nature10350
Sun L, Song L, Wan Q, Wu G, Li X, Wang Y, et al. CMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions. Cell Res. 2015;25:429–44.
pubmed: 25793315
pmcid: 4387561
doi: 10.1038/cr.2015.33
Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T, Van Den Broek NJF, et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature. 2017;544:372–6.
pubmed: 28425994
doi: 10.1038/nature22056
Gwinn DM, Lee AG, Briones-Martin-del-Campo M, Conn CS, Simpson DR, Scott AI, et al. Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to L-asparaginase. Cancer Cell. 2018;33:91–107.e6.
pubmed: 29316436
pmcid: 5761662
doi: 10.1016/j.ccell.2017.12.003
DeNicola GM, Chen P-H, Mullarky E, Sudderth JA, Hu Z, Wu D, et al. NRF2 regulates serine biosynthesis in non–small cell lung cancer. Nat Genet. 2015;47:1475–81. https://doi.org/10.1038/ng.3421 .
doi: 10.1038/ng.3421
pubmed: 26482881
pmcid: 4721512
Kampen KR, Fancello L, Girardi T, Rinaldi G, Planque M, Sulima SO, et al. Translatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells. Nat Commun. 2019;10:2542.
pubmed: 31186416
pmcid: 6559966
doi: 10.1038/s41467-019-10508-2
Girardi T, Vicente C, Cools J, De Keersmaecker K. The genetics and molecular biology of T-ALL. Blood. 2017;129:1113 LP–1123.
doi: 10.1182/blood-2016-10-706465
Kalender Atak Z, Gianfelici V, Hulselmans G, De Keersmaecker K, Devasia AG, Geerdens E, et al. Comprehensive analysis of transcriptome variation uncovers known and novel driver events in T-cell acute lymphoblastic leukemia. PLoS Genet. 2013;9:e1003997.
pmcid: 3868543
doi: 10.1371/journal.pgen.1003997
Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet. 2017;49:1211.
pubmed: 28671688
pmcid: 5535770
doi: 10.1038/ng.3909
Pikman Y, Ocasio-Martinez N, Alexe G, Dimitrov B, Kitara S, Diehl FF, et al. Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy. Leukemia. 2021;36:348–60.
García-Cañaveras JC, Lancho O, Ducker GS, Ghergurovich JM, Xu X, da Silva-Diz V, et al. SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia. Leukemia. 2020;35:377–88.
pubmed: 32382081
pmcid: 7647950
doi: 10.1038/s41375-020-0845-6
Homminga I, Pieters R, Langerak AW, de Rooi JJ, Stubbs A, Verstegen M, et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell. 2011;19:484–97.
pubmed: 21481790
doi: 10.1016/j.ccr.2011.02.008
Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, et al. Characterizing the cancer genome in lung adenocarcinoma. Nature. 2007;450:893–8.
pubmed: 17982442
pmcid: 2538683
doi: 10.1038/nature06358
Kwei KA, Kim YH, Girard L, Kao J, Pacyna-Gengelbach M, Salari K, et al. Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer. Oncogene. 2008;27:3635–40.
pubmed: 18212743
pmcid: 2903002
doi: 10.1038/sj.onc.1211012
Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22:298–305.
pubmed: 26855148
pmcid: 4777652
doi: 10.1038/nm.4045
Baca SC, Takeda DY, Seo J-H, Hwang J, Ku SY, Arafeh R, et al. Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer. Nat Commun. 2021;12:1979.
pubmed: 33785741
pmcid: 8010057
doi: 10.1038/s41467-021-22139-7
Cooper SL, Brown PA. Treatment of pediatric acute lymphoblastic leukemia. Pediatr Clin. 2015;62:61–73.
Davies AH, Beltran H, Zoubeidi A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat Rev Urol. 2018;15:271–86.
pubmed: 29460922
doi: 10.1038/nrurol.2018.22
Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446–54.
pubmed: 29364287
doi: 10.1038/nature25183
Lazzaro D, Price M, de Felice M, Di Lauro R. The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development. 1991;113:1093 LP–1104.
doi: 10.1242/dev.113.4.1093
Guo M, Tomoshige K, Meister M, Muley T, Fukazawa T, Tsuchiya T, et al. Gene signature driving invasive mucinous adenocarcinoma of the lung. EMBO Mol Med. 2017;9:462–81.
pubmed: 28255028
pmcid: 5376761
doi: 10.15252/emmm.201606711
Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.
doi: 10.1038/nature11247
Frith MC, Li MC, Weng Z. Cluster-Buster: finding dense clusters of motifs in DNA sequences. Nucleic Acids Res. 2003;31:3666–8.
pubmed: 12824389
pmcid: 168947
doi: 10.1093/nar/gkg540
Homminga I, Pieters R, Meijerink JPP. NKL homeobox genes in leukemia. Leukemia. 2012;26:572–81. https://doi.org/10.1038/leu.2011.330 .
doi: 10.1038/leu.2011.330
pubmed: 22094586
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Cambridge, Massachusetts: The Broad Institute of Harvard and MIT; 2012. p. 603–7.
Sallach HJ. Formation of serine from hydroxypyruvate and L-alanine. J Biol Chem. 1956;223:1101–8.
pubmed: 13385257
doi: 10.1016/S0021-9258(18)65108-7
Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C, Lee KC, et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell. 2015;27:211–22.
pubmed: 25620030
doi: 10.1016/j.ccell.2014.11.019
Cordes T, Kuna RS, McGregor GH, Khare SV, Gengatharan J, Muthusamy T, et al. 1-Deoxysphingolipid synthesis compromises anchorage-independent growth and plasma membrane endocytosis in cancer cells. J Lipid Res. 2022;63:100281.
pubmed: 36115594
pmcid: 9587408
doi: 10.1016/j.jlr.2022.100281
Maddocks ODK, Labuschagne CF, Adams PD, Vousden KH. Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Mol Cell Cell Press. 2016;61:210–21.
doi: 10.1016/j.molcel.2015.12.014
Kottakis F, Nicolay BN, Roumane A, Karnik R, Gu H, Nagle JM, et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature. 2016;539:390–5.
pubmed: 27799657
pmcid: 5988435
doi: 10.1038/nature20132
Ngo B, Kim E, Osorio-Vasquez V, Doll S, Bustraan S, Liang RJ, et al. Limited environmental serine and glycine confer brain metastasis sensitivity to PHGDH inhibition. Cancer Discov. 2020;10:1352–73.
pubmed: 32571778
pmcid: 7483776
doi: 10.1158/2159-8290.CD-19-1228
Rinaldi G, Pranzini E, Van Elsen J, Broekaert D, Funk CM, Planque M, et al. In vivo evidence for serine biosynthesis-defined sensitivity of lung metastasis, but not of primary breast tumors, to mTORC1 inhibition. Mol Cell. 2021;81:386–97.e7.
pubmed: 33340488
doi: 10.1016/j.molcel.2020.11.027
Jordan EJ, Kim HR, Arcila ME, Barron D, Chakravarty D, Gao J, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 2017;7:596–609.
pubmed: 28336552
pmcid: 5482929
doi: 10.1158/2159-8290.CD-16-1337
Huang RSP, Harries L, Decker B, Hiemenz MC, Murugesan K, Creeden J, et al. Clinicopathologic and genomic landscape of non-small cell lung cancer brain metastases. Oncologist. 2022;27:839–48.
pubmed: 35598205
pmcid: 9526503
doi: 10.1093/oncolo/oyac094
Yamaguchi T, Hosono Y, Yanagisawa K, Takahashi T. NKX2-1/TTF-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression. Cancer Cell. 2013;23:718–23.
pubmed: 23763999
doi: 10.1016/j.ccr.2013.04.002
Tajan M, Hennequart M, Cheung EC, Zani F, Hock AK, Legrave N, et al. Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy. Nat Commun. 2021;12:366.
pubmed: 33446657
pmcid: 7809039
doi: 10.1038/s41467-020-20223-y
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379:2342–50.
pubmed: 30280658
doi: 10.1056/NEJMoa1809697
Fan TWM, Bruntz RC, Yang Y, Song H, Chernyavskaya Y, Deng P, et al. De novo synthesis of serine and glycine fuels purine nucleotide biosynthesis in human lung cancer tissues. J Biol Chem. 2019;294:13464–77.
pubmed: 31337706
pmcid: 6737211
doi: 10.1074/jbc.RA119.008743
Sánchez-Castillo A, Vooijs M, Kampen KR. Linking serine/glycine metabolism to radiotherapy resistance. Cancers. 2021;13:1191.
pubmed: 33801846
pmcid: 8002185
doi: 10.3390/cancers13061191
Wang H, Nicolay BN, Chick JM, Gao X, Geng Y, Ren H, et al. The metabolic function of cyclin D3–CDK6 kinase in cancer cell survival. Nature. 2017;546:426.
pubmed: 28607489
pmcid: 5516959
doi: 10.1038/nature22797
Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 2006;20:2096–109.
pubmed: 16847353
pmcid: 1536060
doi: 10.1101/gad.1450406
Reina-Campos M, Linares JF, Duran A, Cordes T, L’Hermitte A, Badur MG, et al. Increased serine and one-carbon pathway metabolism by PKCλ/ι deficiency promotes neuroendocrine prostate cancer. Cancer Cell. 2019;35:385–400.e9.
pubmed: 30827887
pmcid: 6424636
doi: 10.1016/j.ccell.2019.01.018
Li X, Gracilla D, Cai L, Zhang M, Yu X, Chen X, et al. ATF3 promotes the serine synthesis pathway and tumor growth under dietary serine restriction. Cell Rep. 2021;36:109706.
pubmed: 34551291
pmcid: 8491098
doi: 10.1016/j.celrep.2021.109706
Jeong S, Savino AM, Chirayil R, Barin E, Cheng Y, Park S-M, et al. High fructose drives the serine synthesis pathway in acute myeloid leukemic cells. Cell Metab. 2021;33:145–59.e6.
pubmed: 33357456
doi: 10.1016/j.cmet.2020.12.005
Truong V, Huang S, Dennis J, Lemire M, Zwingerman N, Aïssi D, et al. Blood triglyceride levels are associated with DNA methylation at the serine metabolism gene PHGDH. Sci Rep. 2017;7:11207.
pubmed: 28894120
pmcid: 5593822
doi: 10.1038/s41598-017-09552-z
Ulmer H, Borena W, Rapp K, Klenk J, Strasak A, Diem G, et al. Serum triglyceride concentrations and cancer risk in a large cohort study in Austria. Br J Cancer. 2009;101:1202–6.
pubmed: 19690552
pmcid: 2768093
doi: 10.1038/sj.bjc.6605264
Papachristodoulou A, Rodriguez-Calero A, Panja S, Margolskee E, Virk RK, Milner TA, et al. NKX3.1 localization to mitochondria suppresses prostate cancer initiation. Cancer Discov. 2021;11:2316 LP–2333.
doi: 10.1158/2159-8290.CD-20-1765
Smith R, Owen LA, Trem DJ, Wong JS, Whangbo JS, Golub TR, et al. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma. Cancer Cell. 2006;9:405–16.
pubmed: 16697960
doi: 10.1016/j.ccr.2006.04.004
Shibata K, Kajiyama H, Yamamoto E, Terauchi M, Ino K, Nawa A, et al. Establishment and characterization of an ovarian yolk sac tumor cell line reveals possible involvement of Nkx2.5 in tumor development. Oncology. 2008;74:104–11.
pubmed: 18547965
doi: 10.1159/000139138
Gelmann EP, Bowen C, Bubendorf L. Expression of NKX3.1 in normal and malignant tissues. Prostate. 2003;55:111–7.
pubmed: 12661036
doi: 10.1002/pros.10210
Tasdogan A, Ubellacker JM, Morrison SJ. Redox regulation in cancer cells during metastasis. Cancer Discov. 2021;11:2682–92.
pubmed: 34649956
pmcid: 8563381
doi: 10.1158/2159-8290.CD-21-0558
Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature. 2015;527:186–91.
pubmed: 26466563
pmcid: 4644103
doi: 10.1038/nature15726
Rathore R, Caldwell KE, Schutt C, Brashears CB, Prudner BC, Ehrhardt WR, et al. Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma. Cell Rep. 2021;34:108678.
pubmed: 33503424
pmcid: 8552368
doi: 10.1016/j.celrep.2020.108678
Mei S, Qin Q, Wu Q, Sun H, Zheng R, Zang C, et al. Cistrome Data Browser: a data portal for ChIP-Seq and chromatin accessibility data in human and mouse. Nucleic Acids Res. 2017;45:D658–62.
pubmed: 27789702
doi: 10.1093/nar/gkw983
Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. Genome Res. 2002;12:996–1006.
pubmed: 12045153
pmcid: 186604
doi: 10.1101/gr.229102
Hellmann MD, Nathanson T, Rizvi H, Creelan BC, Sanchez-Vega F, Ahuja A, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell. 2018;33:843–52.e4.
pubmed: 29657128
pmcid: 5953836
doi: 10.1016/j.ccell.2018.03.018
Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol. 2018;36:2872–8.
pubmed: 30125216
doi: 10.1200/JCO.2018.79.0006
Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017;376:2109–21.
pubmed: 28445112
doi: 10.1056/NEJMoa1616288
Vavalà T, Monica V, Lo Iacono M, Mele T, Busso S, Righi L, et al. Precision medicine in age-specific non-small-cell-lung-cancer patients: integrating biomolecular results into clinical practice—a new approach to improve personalized translational research. Lung Cancer. 2017;107:84–90.
pubmed: 27346245
doi: 10.1016/j.lungcan.2016.05.021
Aerts S, Van Loo P, Thijs G, Mayer H, de Martin R, Moreau Y, et al. TOUCAN 2: the all-inclusive open source workbench for regulatory sequence analysis. Nucleic Acids Res. 2005;33:W393–6.
pubmed: 15980497
pmcid: 1160115
doi: 10.1093/nar/gki354
Nagel S, Pommerenke C, Scherr M, Meyer C, Kaufmann M, Battmer K, et al. NKL homeobox gene activities in hematopoietic stem cells, T-cell development and T-cell leukemia. PLoS ONE. 2017;12:e0171164.
pubmed: 28151996
pmcid: 5289504
doi: 10.1371/journal.pone.0171164
Nassar ZD, Mah CY, Dehairs J, Burvenich IJG, Irani S, Centenera MM, et al. Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis. eLife. 2020;9:e54166.
pubmed: 32686647
pmcid: 7386908
doi: 10.7554/eLife.54166
Krueger F, Andrews SR. Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics. 2011;27:1571–2.
pubmed: 21493656
pmcid: 3102221
doi: 10.1093/bioinformatics/btr167
Akalin A, Kormaksson M, Li S, Garrett-Bakelman FE, Figueroa ME, Melnick A, et al. methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. Genome Biol. 2012;13:R87.
pubmed: 23034086
pmcid: 3491415
doi: 10.1186/gb-2012-13-10-r87
Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7:16878.
pubmed: 29203879
pmcid: 5715110
doi: 10.1038/s41598-017-17204-5