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Epigenetic markers and therapeutic targets for metastasis

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Abstract

The last few years have seen an increasing number of discoveries which collectively demonstrate that histone and DNA modifying enzyme modulate different stages of metastasis. Moreover, epigenomic alterations can now be measured at multiple scales of analysis and are detectable in human tumors or liquid biopsies. Malignant cell clones with a proclivity for relapse in certain organs may arise in the primary tumor as a consequence of epigenomic alterations which cause a loss in lineage integrity. These alterations may occur due to genetic aberrations acquired during tumor progression or concomitant to therapeutic response. Moreover, evolution of the stroma can also alter the epigenome of cancer cells. In this review, we highlight current knowledge with a particular emphasis on leveraging chromatin and DNA modifying mechanisms as biomarkers of disseminated disease and as therapeutic targets to treat metastatic cancers.

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References

  1. Massague, J., & Obenauf, A. C. (2016). Metastatic colonization by circulating tumour cells. Nature, 529(7586), 298–306. https://doi.org/10.1038/nature17038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lambert, A. W., Pattabiraman, D. R., & Weinberg, R. A. (2017). Emerging biological principles of metastasis. Cell, 168(4), 670–691. https://doi.org/10.1016/j.cell.2016.11.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Celia-Terrassa, T., & Kang, Y. (2018). Metastatic niche functions and therapeutic opportunities. Nature Cell Biology, 20(8), 868–877. https://doi.org/10.1038/s41556-018-0145-9

    Article  CAS  PubMed  Google Scholar 

  4. Quail, D. F., & Joyce, J. A. (2017). The microenvironmental landscape of brain tumors. Cancer Cell, 31(3), 326–341. https://doi.org/10.1016/j.ccell.2017.02.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nguyen, B., Fong, C., Luthra, A., Smith, S. A., DiNatale, R. G., Nandakumar, S., et al. (2022). Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell, 185(3), 563–575.e511. https://doi.org/10.1016/j.cell.2022.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Aftimos, P., Oliveira, M., Irrthum, A., Fumagalli, D., Sotiriou, C., Gal-Yam, E. N., et al. (2021). Genomic and Transcriptomic analyses of breast cancer primaries and matched metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative. Cancer Discovery, 11(11), 2796–2811. https://doi.org/10.1158/2159-8290.CD-20-1647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Priestley, P., Baber, J., Lolkema, M. P., Steeghs, N., de Bruijn, E., Shale, C., et al. (2019). Pan-cancer whole-genome analyses of metastatic solid tumours. Nature, 575(7781), 210–216. https://doi.org/10.1038/s41586-019-1689-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Patel, S. A., & Vanharanta, S. (2017). Epigenetic determinants of metastasis. Molecular Oncology, 11(1), 79–96. https://doi.org/10.1016/j.molonc.2016.09.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Marine, J. C., Dawson, S. J., & Dawson, M. A. (2020). Non-genetic mechanisms of therapeutic resistance in cancer. Nature Reviews Cancer, 20(12), 743–756. https://doi.org/10.1038/s41568-020-00302-4

    Article  CAS  PubMed  Google Scholar 

  10. Chen, J. F., & Yan, Q. (2021). The roles of epigenetics in cancer progression and metastasis. The Biochemical Journal, 478(17), 3373–3393. https://doi.org/10.1042/bcj20210084

    Article  CAS  PubMed  Google Scholar 

  11. Feinberg, A. P., & Tycko, B. (2004). The history of cancer epigenetics. Nature Reviews. Cancer, 4(2), 143–153. https://doi.org/10.1038/nrc1279

    Article  CAS  PubMed  Google Scholar 

  12. Plass, C., Pfister, S. M., Lindroth, A. M., Bogatyrova, O., Claus, R., & Lichter, P. (2013). Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nature Reviews Genetics, 14(11), 765–780. https://doi.org/10.1038/nrg3554

    Article  CAS  PubMed  Google Scholar 

  13. Feinberg, A. P., Koldobskiy, M. A., & Göndör, A. (2016). Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nature Reviews Genetics, 17(5), 284–299. https://doi.org/10.1038/nrg.2016.13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Michalak, E. M., Burr, M. L., Bannister, A. J., & Dawson, M. A. (2019). The roles of DNA, RNA and histone methylation in ageing and cancer. Nature Reviews Molecular Cell Biology, 20(10), 573–589. https://doi.org/10.1038/s41580-019-0143-1

    Article  CAS  PubMed  Google Scholar 

  15. Alix-Panabières, C., & Pantel, K. (2021). Liquid biopsy: From discovery to clinical application. Cancer Discovery, 11(4), 858–873. https://doi.org/10.1158/2159-8290.Cd-20-1311

    Article  PubMed  Google Scholar 

  16. Sadeh, R., Sharkia, I., Fialkoff, G., Rahat, A., Gutin, J., Chappleboim, A., et al. (2021). ChIP-seq of plasma cell-free nucleosomes identifies gene expression programs of the cells of origin. Nature Biotechnology, 39(5), 586–598. https://doi.org/10.1038/s41587-020-00775-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jamshidi, A., Liu, M. C., Klein, E. A., Venn, O., Hubbell, E., Beausang, J. F., et al. (2022). Evaluation of cell-free DNA approaches for multi-cancer early detection. Cancer Cell, 40(12), 1537–1549.e1512. https://doi.org/10.1016/j.ccell.2022.10.022

    Article  CAS  PubMed  Google Scholar 

  18. Ring, A., Nguyen-Sträuli, B. D., Wicki, A., & Aceto, N. (2022). Biology, vulnerabilities and clinical applications of circulating tumour cells. Nature Reviews. Cancer, 1-17. https://doi.org/10.1038/s41568-022-00536-4

  19. Buscail, E., Chiche, L., Laurent, C., Vendrely, V., Denost, Q., Denis, J., et al. (2019). Tumor-proximal liquid biopsy to improve diagnostic and prognostic performances of circulating tumor cells. Molecular Oncology, 13(9), 1811–1826. https://doi.org/10.1002/1878-0261.12534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Costa, C., & Dávila-Ibáñez, A. B. (2020). Methodology for the isolation and analysis of CTCs. Advances in Experimental Medicine and Biology, 1220, 45–59. https://doi.org/10.1007/978-3-030-35805-1_4

    Article  CAS  PubMed  Google Scholar 

  21. Simpson, K. L., Stoney, R., Frese, K. K., Simms, N., Rowe, W., Pearce, S. P., et al. (2020). A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity. Nat Cancer, 1(4), 437–451. https://doi.org/10.1038/s43018-020-0046-2

    Article  CAS  PubMed  Google Scholar 

  22. Hong, X., Roh, W., Sullivan, R. J., Wong, K. H. K., Wittner, B. S., Guo, H., et al. (2021). The lipogenic regulator SREBP2 induces transferrin in circulating melanoma cells and suppresses ferroptosis. Cancer Discovery, 11(3), 678–695. https://doi.org/10.1158/2159-8290.Cd-19-1500

    Article  CAS  PubMed  Google Scholar 

  23. Zhang, L., Ridgway, L. D., Wetzel, M. D., Ngo, J., Yin, W., Kumar, D., et al. (2013). The identification and characterization of breast cancer CTCs competent for brain metastasis. Science Translational Medicine, 5(180), 180ra148. https://doi.org/10.1126/scitranslmed.3005109

    Article  CAS  Google Scholar 

  24. Baccelli, I., Schneeweiss, A., Riethdorf, S., Stenzinger, A., Schillert, A., Vogel, V., et al. (2013). Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nature Biotechnology, 31(6), 539–544. https://doi.org/10.1038/nbt.2576

    Article  CAS  PubMed  Google Scholar 

  25. Padmanaban, V., Krol, I., Suhail, Y., Szczerba, B. M., Aceto, N., Bader, J. S., et al. (2019). E-cadherin is required for metastasis in multiple models of breast cancer. Nature, 573(7774), 439–444. https://doi.org/10.1038/s41586-019-1526-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ubellacker, J. M., Tasdogan, A., Ramesh, V., Shen, B., Mitchell, E. C., Martin-Sandoval, M. S., et al. (2020). Lymph protects metastasizing melanoma cells from ferroptosis. Nature, 585(7823), 113–118. https://doi.org/10.1038/s41586-020-2623-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Piskounova, E., Agathocleous, M., Murphy, M. M., Hu, Z., Huddlestun, S. E., Zhao, Z., et al. (2015). Oxidative stress inhibits distant metastasis by human melanoma cells. Nature, 527(7577), 186–191. https://doi.org/10.1038/nature15726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sprouse, M. L., Welte, T., Boral, D., Liu, H. N., Yin, W., Vishnoi, M., et al. (2019). PMN-MDSCs enhance CTC metastatic properties through reciprocal interactions via ROS/Notch/Nodal signaling. International Journal of Molecular Sciences, 20(8). https://doi.org/10.3390/ijms20081916

  29. Bowley, T. Y., Lagutina, I. V., Francis, C., Sivakumar, S., Selwyn, R. G., Taylor, E., et al. (2022). The RPL/RPS gene signature of melanoma CTCs associates with brain metastasis. Cancer Research Communications, 2(11), 1436–1448. https://doi.org/10.1158/2767-9764.crc-22-0337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ebright, R. Y., Lee, S., Wittner, B. S., Niederhoffer, K. L., Nicholson, B. T., Bardia, A., et al. (2020). Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis. Science, 367(6485), 1468–1473. https://doi.org/10.1126/science.aay0939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cai, W. L., Chen, J. F., Chen, H., Wingrove, E., Kurley, S. J., Chan, L. H., et al. (2022). Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation. Elife, 11. https://doi.org/10.7554/eLife.78163

  32. Aho, E. R., Wang, J., Gogliotti, R. D., Howard, G. C., Phan, J., Acharya, P., et al. (2019). Displacement of WDR5 from chromatin by a WIN site inhibitor with picomolar affinity. Cell Reports, 26(11), 2916–2928. e2913. https://doi.org/10.1016/j.celrep.2019.02.047

    Article  CAS  PubMed  Google Scholar 

  33. Guarnaccia, A. D., & Tansey, W. P. (2018). Moonlighting with WDR5: A cellular multitasker. Journal of Clinical Medicine, 7(2). https://doi.org/10.3390/jcm7020021

  34. Schuster, E., Taftaf, R., Reduzzi, C., Albert, M. K., Romero-Calvo, I., & Liu, H. (2021). Better together: circulating tumor cell clustering in metastatic cancer. Trends Cancer, 7(11), 1020–1032. https://doi.org/10.1016/j.trecan.2021.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Aceto, N., Bardia, A., Miyamoto, D. T., Donaldson, M. C., Wittner, B. S., Spencer, J. A., et al. (2014). Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell, 158(5), 1110–1122. https://doi.org/10.1016/j.cell.2014.07.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu, X., Taftaf, R., Kawaguchi, M., Chang, Y. F., Chen, W., Entenberg, D., et al. (2019). Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models. Cancer Discovery, 9(1), 96–113. https://doi.org/10.1158/2159-8290.Cd-18-0065

    Article  PubMed  Google Scholar 

  37. Wei, R. R., Sun, D. N., Yang, H., Yan, J., Zhang, X., Zheng, X. L., et al. (2018). CTC clusters induced by heparanase enhance breast cancer metastasis. Acta Pharmacologica Sinica, 39(8), 1326–1337. https://doi.org/10.1038/aps.2017.189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wrenn, E. D., Yamamoto, A., Moore, B. M., Huang, Y., McBirney, M., Thomas, A. J., et al. (2020). Regulation of collective metastasis by nanolumenal signaling. Cell, 183(2), 395–410.e319. https://doi.org/10.1016/j.cell.2020.08.045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gkountela, S., Castro-Giner, F., Szczerba, B. M., Vetter, M., Landin, J., Scherrer, R., et al. (2019). Circulating tumor cell clustering shapes DNA methylation to enable metastasis seeding. Cell, 176(1-2), 98–112.e114. https://doi.org/10.1016/j.cell.2018.11.046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chang, P. H., Chen, M. C., Tsai, Y. P., Tan, G. Y. T., Hsu, P. H., Jeng, Y. M., et al. (2021). Interplay between desmoglein2 and hypoxia controls metastasis in breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 118(3). https://doi.org/10.1073/pnas.2014408118

  41. Szczerba, B. M., Castro-Giner, F., Vetter, M., Krol, I., Gkountela, S., Landin, J., et al. (2019). Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature, 566(7745), 553–557. https://doi.org/10.1038/s41586-019-0915-y

    Article  CAS  PubMed  Google Scholar 

  42. Chimonidou, M., Strati, A., Malamos, N., Kouneli, S., Georgoulias, V., & Lianidou, E. (2017). Direct comparison study of DNA methylation markers in EpCAM-positive circulating tumour cells, corresponding circulating tumour DNA, and paired primary tumours in breast cancer. Oncotarget, 8(42), 72054–72068. https://doi.org/10.18632/oncotarget.18679

    Article  PubMed  PubMed Central  Google Scholar 

  43. Strati, A., Zavridou, M., Kallergi, G., Politaki, E., Kuske, A., Gorges, T. M., et al. (2021). A comprehensive molecular analysis of in vivo isolated EpCAM-positive circulating tumor cells in breast cancer. Clinical Chemistry, 67(10), 1395–1405. https://doi.org/10.1093/clinchem/hvab099

    Article  PubMed  Google Scholar 

  44. Pixberg, C. F., Raba, K., Müller, F., Behrens, B., Honisch, E., Niederacher, D., et al. (2017). Analysis of DNA methylation in single circulating tumor cells. Oncogene, 36(23), 3223–3231. https://doi.org/10.1038/onc.2016.480

    Article  CAS  PubMed  Google Scholar 

  45. Cheng, H. H., Plets, M., Li, H., Higano, C. S., Tangen, C. M., Agarwal, N., et al. (2018). Circulating microRNAs and treatment response in the Phase II SWOG S0925 study for patients with new metastatic hormone-sensitive prostate cancer. Prostate, 78(2), 121–127. https://doi.org/10.1002/pros.23452

    Article  CAS  PubMed  Google Scholar 

  46. Aiello, N. M., Maddipati, R., Norgard, R. J., Balli, D., Li, J., Yuan, S., et al. (2018). EMT subtype influences epithelial plasticity and mode of cell migration. Developmental Cell, 45(6), 681–695.e684. https://doi.org/10.1016/j.devcel.2018.05.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cheung, K. J., Padmanaban, V., Silvestri, V., Schipper, K., Cohen, J. D., Fairchild, A. N., et al. (2016). Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proceedings of the National Academy of Sciences of the United States of America, 113(7), E854–E863. https://doi.org/10.1073/pnas.1508541113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lim, A. R., & Ghajar, C. M. (2022). Thorny ground, rocky soil: Tissue-specific mechanisms of tumor dormancy and relapse. Seminars in Cancer Biology, 78, 104–123. https://doi.org/10.1016/j.semcancer.2021.05.007

    Article  CAS  PubMed  Google Scholar 

  49. Sosa, M. S., Parikh, F., Maia, A. G., Estrada, Y., Bosch, A., Bragado, P., et al. (2015). NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes. Nature Communications, 6, 6170. https://doi.org/10.1038/ncomms7170

    Article  CAS  PubMed  Google Scholar 

  50. Borgen, E., Rypdal, M. C., Sosa, M. S., Renolen, A., Schlichting, E., Lønning, P. E., et al. (2018). NR2F1 stratifies dormant disseminated tumor cells in breast cancer patients. Breast Cancer Research, 20(1), 120. https://doi.org/10.1186/s13058-018-1049-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gawrzak, S., Rinaldi, L., Gregorio, S., Arenas, E. J., Salvador, F., Urosevic, J., et al. (2018). MSK1 regulates luminal cell differentiation and metastatic dormancy in ER(+) breast cancer. Nature Cell Biology, 20(2), 211–221. https://doi.org/10.1038/s41556-017-0021-z

    Article  CAS  PubMed  Google Scholar 

  52. Clements, M. E., Holtslander, L., Edwards, C., Todd, V., Dooyema, S. D. R., Bullock, K., et al. (2021). HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer. Oncogene, 40(34), 5314–5326. https://doi.org/10.1038/s41388-021-01931-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Johnson, R. W., Finger, E. C., Olcina, M. M., Vilalta, M., Aguilera, T., Miao, Y., et al. (2016). Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nature Cell Biology, 18(10), 1078–1089. https://doi.org/10.1038/ncb3408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sun, D., Singh, D. K., Carcamo, S., Filipescu, D., Khalil, B., Huang, X., et al. (2022). MacroH2A impedes metastatic growth by enforcing a discrete dormancy program in disseminated cancer cells. Science Advances, 8(48), eabo0876. https://doi.org/10.1126/sciadv.abo0876

    Article  CAS  PubMed  Google Scholar 

  55. Shen, M., & Kang, Y. (2020). Stresses in the metastatic cascade: Molecular mechanisms and therapeutic opportunities. Genes & Development, 34(23-24), 1577–1598. https://doi.org/10.1101/gad.343251.120

    Article  CAS  Google Scholar 

  56. Nishida, J., Momoi, Y., Miyakuni, K., Tamura, Y., Takahashi, K., Koinuma, D., et al. (2020). Epigenetic remodelling shapes inflammatory renal cancer and neutrophil-dependent metastasis. Nature Cell Biology, 22(4), 465–475. https://doi.org/10.1038/s41556-020-0491-2

    Article  CAS  PubMed  Google Scholar 

  57. Zhang, M., Liu, Z. Z., Aoshima, K., Cai, W. L., Sun, H., Xu, T., et al. (2022). CECR2 drives breast cancer metastasis by promoting NF-kappaB signaling and macrophage-mediated immune suppression. Science Translational Medicine, 14(630), eabf5473. https://doi.org/10.1126/scitranslmed.abf5473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Szekely, B., Bossuyt, V., Li, X., Wali, V. B., Patwardhan, G. A., Frederick, C., et al. (2018). Immunological differences between primary and metastatic breast cancer. Annals of Oncology, 29(11), 2232–2239. https://doi.org/10.1093/annonc/mdy399

    Article  CAS  PubMed  Google Scholar 

  59. Cao, J., & Yan, Q. (2020). Cancer epigenetics, tumor immunity, and immunotherapy. Trends Cancer, 6(7), 580–592. https://doi.org/10.1016/j.trecan.2020.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Micevic, G., Bosenberg, M. W., & Yan, Q. (2022). The crossroads of cancer epigenetics and immune checkpoint therapy. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-22-0784

  61. Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J. R., Cole, P. A., et al. (2004). Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 119(7), 941–953.

    Article  CAS  PubMed  Google Scholar 

  62. Sheng, W., LaFleur, M. W., Nguyen, T. H., Chen, S., Chakravarthy, A., Conway, J. R., et al. (2018). LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell, 174(3), 549–563. e519. https://doi.org/10.1016/j.cell.2018.05.052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang, S. M., Cai, W. L., Liu, X., Thakral, D., Luo, J., Chan, L. H., et al. (2021). KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements. Nature, 598(7882), 682–687. https://doi.org/10.1038/s41586-021-03994-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hu, H., Khodadadi-Jamayran, A., Dolgalev, I., Cho, H., Badri, S., Chiriboga, L. A., et al. (2021). Targeting the Atf7ip-Setdb1 complex augments antitumor immunity by boosting tumor immunogenicity. Cancer Immunology Research, 9(11), 1298-1315. https://doi.org/10.1158/2326-6066.CIR-21-0543.

  65. Lin, J., Guo, D., Liu, H., Zhou, W., Wang, C., Muller, I., et al. (2021). The SETDB1-TRIM28 complex suppresses antitumor immunity. Cancer Immunology Research, 9(12), 1413–1424. https://doi.org/10.1158/2326-6066.CIR-21-0754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Guo, E., Xiao, R., Wu, Y., Lu, F., Liu, C., Yang, B., et al. (2022). WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway. The Journal of Experimental Medicine, 219(1). https://doi.org/10.1084/jem.20210789

  67. Griffin, G. K., Wu, J., Iracheta-Vellve, A., Patti, J. C., Hsu, J., Davis, T., et al. (2021). Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity. Nature, 595(7866), 309–314. https://doi.org/10.1038/s41586-021-03520-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Li, J., Yuan, S., Norgard, R. J., Yan, F., Sun, Y. H., Kim, I. K., et al. (2021). Epigenetic and transcriptional control of the epidermal growth factor receptor regulates the tumor immune microenvironment in pancreatic cancer. Cancer Discovery, 11(3), 736–753. https://doi.org/10.1158/2159-8290.CD-20-0519

    Article  PubMed  Google Scholar 

  69. Chan, I. S., Knutsdottir, H., Ramakrishnan, G., Padmanaban, V., Warrier, M., Ramirez, J. C., et al. (2020). Cancer cells educate natural killer cells to a metastasis-promoting cell state. The Journal of Cell Biology, 219(9). https://doi.org/10.1083/jcb.202001134

  70. Garcia-Recio, S., Hinoue, T., Wheeler, G. L., Kelly, B. J., Garrido-Castro, A. C., Pascual, T., et al. (2023). Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis. Nat Cancer, 4(1), 128–147. https://doi.org/10.1038/s43018-022-00491-x

    Article  CAS  PubMed  Google Scholar 

  71. So, J. Y., Skrypek, N., Yang, H. H., Merchant, A. S., Nelson, G. W., Chen, W. D., et al. (2020). Induction of DNMT3B by PGE2 and IL6 at distant metastatic sites promotes epigenetic modification and breast cancer colonization. Cancer Research, 80(12), 2612–2627. https://doi.org/10.1158/0008-5472.Can-19-3339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Fukumoto, T., Fatkhutdinov, N., Zundell, J. A., Tcyganov, E. N., Nacarelli, T., Karakashev, S., et al. (2019). HDAC6 inhibition synergizes with anti-PD-L1 therapy in ARID1A-inactivated ovarian cancer. Cancer Research, 79(21), 5482–5489. https://doi.org/10.1158/0008-5472.CAN-19-1302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gupta, P. B., Pastushenko, I., Skibinski, A., Blanpain, C., & Kuperwasser, C. (2019). Phenotypic plasticity: Driver of cancer initiation, progression, and therapy resistance. Cell Stem Cell, 24(1), 65–78. https://doi.org/10.1016/j.stem.2018.11.011

    Article  CAS  PubMed  Google Scholar 

  74. Sequist, L. V., Waltman, B. A., Dias-Santagata, D., Digumarthy, S., Turke, A. B., Fidias, P., et al. (2011). Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science Translational Medicine, 3(75), 75ra26. https://doi.org/10.1126/scitranslmed.3002003

    Article  PubMed  PubMed Central  Google Scholar 

  75. Jang, M. H., Kim, H. J., Kim, E. J., Chung, Y. R., & Park, S. Y. (2015). Expression of epithelial-mesenchymal transition-related markers in triple-negative breast cancer: ZEB1 as a potential biomarker for poor clinical outcome. Human Pathology, 46(9), 1267–1274. https://doi.org/10.1016/j.humpath.2015.05.010

    Article  CAS  PubMed  Google Scholar 

  76. Cheung, S. Y., Boey, Y. J., Koh, V. C., Thike, A. A., Lim, J. C., Iqbal, J., et al. (2015). Role of epithelial-mesenchymal transition markers in triple-negative breast cancer. Breast Cancer Research and Treatment, 152(3), 489–498. https://doi.org/10.1007/s10549-015-3485-1

    Article  CAS  PubMed  Google Scholar 

  77. Rasheed, Z. A., Yang, J., Wang, Q., Kowalski, J., Freed, I., Murter, C., et al. (2010). Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. Journal of the National Cancer Institute, 102(5), 340–351. https://doi.org/10.1093/jnci/djp535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wu, S. Z., Al-Eryani, G., Roden, D. L., Junankar, S., Harvey, K., Andersson, A., et al. (2021). A single-cell and spatially resolved atlas of human breast cancers. Nature Genetics, 53(9), 1334–1347. https://doi.org/10.1038/s41588-021-00911-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Grasset, E. M., Dunworth, M., Sharma, G., Loth, M., Tandurella, J., Cimino-Mathews, A., et al. (2022). Triple-negative breast cancer metastasis involves complex epithelial-mesenchymal transition dynamics and requires vimentin. Science Translational Medicine, 14(656), eabn7571. https://doi.org/10.1126/scitranslmed.abn7571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yang, J., Antin, P., Berx, G., Blanpain, C., Brabletz, T., Bronner, M., et al. (2020). Guidelines and definitions for research on epithelial-mesenchymal transition. Nature Reviews Molecular Cell Biology, 21(6), 341–352. https://doi.org/10.1038/s41580-020-0237-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Skrypek, N., Goossens, S., De Smedt, E., Vandamme, N., & Berx, G. (2017). Epithelial-to-mesenchymal transition: Epigenetic reprogramming driving cellular plasticity. Trends in Genetics, 33(12), 943–959. https://doi.org/10.1016/j.tig.2017.08.004

    Article  CAS  PubMed  Google Scholar 

  82. Yuan, S., Natesan, R., Sanchez-Rivera, F. J., Li, J., Bhanu, N. V., Yamazoe, T., et al. (2020). Global regulation of the histone mark H3K36me2 underlies epithelial plasticity and metastatic progression. Cancer Discovery, 10(6), 854–871. https://doi.org/10.1158/2159-8290.Cd-19-1299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhang, Y., Donaher, J. L., Das, S., Li, X., Reinhardt, F., Krall, J. A., et al. (2022). Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis. Nature Cell Biology, 24(4), 554–564. https://doi.org/10.1038/s41556-022-00877-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lee, J. E., Wang, C., Xu, S., Cho, Y. W., Wang, L., Feng, X., et al. (2013). H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. Elife, 2, e01503. https://doi.org/10.7554/eLife.01503

    Article  PubMed  PubMed Central  Google Scholar 

  85. Chen, H., Tu, S. W., & Hsieh, J. T. (2005). Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer. The Journal of Biological Chemistry, 280(23), 22437–22444. https://doi.org/10.1074/jbc.m501379200

    Article  CAS  PubMed  Google Scholar 

  86. Xie, D., Gore, C., Liu, J., Pong, R. C., Mason, R., Hao, G., et al. (2010). Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis. Proceedings of the National Academy of Sciences of the United States of America, 107(6), 2485–2490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Min, J., Zaslavsky, A., Fedele, G., McLaughlin, S. K., Reczek, E. E., De Raedt, T., et al. (2010). An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nature Medicine, 16(3), 286–294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cui, J., Zhang, C., Lee, J. E., Bartholdy, B. A., Yang, D., Liu, Y., et al. (2023). MLL3 loss drives metastasis by promoting a hybrid epithelial-mesenchymal transition state. Nature Cell Biology. https://doi.org/10.1038/s41556-022-01045-0

  89. Balanis, N. G., Sheu, K. M., Esedebe, F. N., Patel, S. J., Smith, B. A., Park, J. W., et al. (2019). Pan-cancer convergence to a small-cell neuroendocrine phenotype that shares susceptibilities with hematological malignancies. Cancer Cell, 36(1), 17–34.e17. https://doi.org/10.1016/j.ccell.2019.06.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Quintanal-Villalonga, A., Taniguchi, H., Zhan, Y. A., Hasan, M. M., Chavan, S. S., Meng, F., et al. (2021). Multiomic analysis of lung tumors defines pathways activated in neuroendocrine transformation. Cancer Discovery, 11(12), 3028–3047. https://doi.org/10.1158/2159-8290.Cd-20-1863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Beltran, H., Romanel, A., Conteduca, V., Casiraghi, N., Sigouros, M., Franceschini, G. M., et al. (2020). Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer. The Journal of Clinical Investigation, 130(4), 1653–1668. https://doi.org/10.1172/jci131041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Chemi, F., Pearce, S. P., Clipson, A., Hill, S. M., Conway, A. M., Richardson, S. A., et al. (2022). cfDNA methylome profiling for detection and subtyping of small cell lung cancers. Nat Cancer, 3(10), 1260–1270. https://doi.org/10.1038/s43018-022-00415-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Beltran, H., Prandi, D., Mosquera, J. M., Benelli, M., Puca, L., Cyrta, J., et al. (2016). Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nature Medicine, 22(3), 298–305. https://doi.org/10.1038/nm.4045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Varambally, S., Dhanasekaran, S. M., Zhou, M., Barrette, T. R., Kumar-Sinha, C., Sanda, M. G., et al. (2002). The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature, 419(6907), 624–629. https://doi.org/10.1038/nature01075

    Article  CAS  PubMed  Google Scholar 

  95. Ku, S. Y., Rosario, S., Wang, Y., Mu, P., Seshadri, M., Goodrich, Z. W., et al. (2017). Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science, 355(6320), 78–83. https://doi.org/10.1126/science.aah4199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Dardenne, E., Beltran, H., Benelli, M., Gayvert, K., Berger, A., Puca, L., et al. (2016). N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell, 30(4), 563–577. https://doi.org/10.1016/j.ccell.2016.09.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Xin, L. (2021). EZH2 accompanies prostate cancer progression. Nature Cell Biology, 23(9), 934–936. https://doi.org/10.1038/s41556-021-00744-4

    Article  CAS  PubMed  Google Scholar 

  98. Jung, E., Alfonso, J., Monyer, H., Wick, W., & Winkler, F. (2020). Neuronal signatures in cancer. International Journal of Cancer, 147(12), 3281–3291. https://doi.org/10.1002/ijc.33138

    Article  CAS  PubMed  Google Scholar 

  99. Wingrove, E., Liu, Z. Z., Patel, K. D., Arnal-Estapé, A., Cai, W. L., Melnick, M. A., et al. (2019). Transcriptomic hallmarks of tumor plasticity and stromal interactions in brain metastasis. Cell Reports, 27(4), 1277–1292.e1277. https://doi.org/10.1016/j.celrep.2019.03.085

    Article  CAS  PubMed  Google Scholar 

  100. Peluffo, G., Subedee, A., Harper, N. W., Kingston, N., Jovanović, B., Flores, F., et al. (2019). EN1 is a transcriptional dependency in triple-negative breast cancer associated with brain metastasis. Cancer Research, 79(16), 4173–4183. https://doi.org/10.1158/0008-5472.Can-18-3264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Denny, S. K., Yang, D., Chuang, C. H., Brady, J. J., Lim, J. S., Grüner, B. M., et al. (2016). Nfib promotes metastasis through a widespread increase in chromatin accessibility. Cell, 166(2), 328–342. https://doi.org/10.1016/j.cell.2016.05.052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Langille, E., Al-Zahrani, K. N., Ma, Z., Liang, M., Uuskula-Reimand, L., Espin, R., et al. (2022). Loss of epigenetic regulation disrupts lineage integrity, induces aberrant alveogenesis, and promotes breast cancer. Cancer Discovery, 12(12), 2930–2953. https://doi.org/10.1158/2159-8290.Cd-21-0865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Al Bakir, M., Huebner, A., Martínez-Ruiz, C., Grigoriadis, K., Watkins, T. B. K., Pich, O., et al. (2023). The evolution of non-small cell lung cancer metastases in TRACERx. Nature. https://doi.org/10.1038/s41586-023-05729-x

  104. Pierce, S. E., Granja, J. M., Corces, M. R., Brady, J. J., Tsai, M. K., Pierce, A. B., et al. (2021). LKB1 inactivation modulates chromatin accessibility to drive metastatic progression. Nature Cell Biology, 23(8), 915-924. https://doi.org/10.1038/s41556-021-00728-4.

  105. Vanharanta, S., Shu, W., Brenet, F., Hakimi, A. A., Heguy, A., Viale, A., et al. (2013). Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer. Nature Medicine, 19(1), 50–56. https://doi.org/10.1038/nm.3029

    Article  CAS  PubMed  Google Scholar 

  106. Hansen, K. D., Timp, W., Bravo, H. C., Sabunciyan, S., Langmead, B., McDonald, O. G., et al. (2011). Increased methylation variation in epigenetic domains across cancer types. Nature Genetics, 43(8), 768–775. https://doi.org/10.1038/ng.865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chen, S., Petricca, J., Ye, W., Guan, J., Zeng, Y., Cheng, N., et al. (2022). The cell-free DNA methylome captures distinctions between localized and metastatic prostate tumors. Nature Communications, 13(1), 6467. https://doi.org/10.1038/s41467-022-34012-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Li, W., Guo, L., Tang, W., Ma, Y., Wang, X., Shao, Y., et al. (2021). Identification of DNA methylation biomarkers for risk of liver metastasis in early-stage colorectal cancer. Clinical Epigenetics, 13(1), 126. https://doi.org/10.1186/s13148-021-01108-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Corces, M. R., Granja, J. M., Shams, S., Louie, B. H., Seoane, J. A., Zhou, W., et al. (2018). The chromatin accessibility landscape of primary human cancers. Science, 362(6413). https://doi.org/10.1126/science.aav1898

  110. Cai, W. L., Greer, C. B., Chen, J. F., Arnal-Estapé, A., Cao, J., Yan, Q., et al. (2020). Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain. BMC Medical Genomics, 13(1), 33. https://doi.org/10.1186/s12920-020-0695-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lee, J. H., & Massagué, J. (2022). TGF-β in developmental and fibrogenic EMTs. Seminars in Cancer Biology, 86(Pt 2), 136–145. https://doi.org/10.1016/j.semcancer.2022.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. McDonald, O. G., Wu, H., Timp, W., Doi, A., & Feinberg, A. P. (2011). Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nature Structural & Molecular Biology, 18(8), 867–874. https://doi.org/10.1038/nsmb.2084

    Article  CAS  Google Scholar 

  113. Song, Y., Zhang, H., Yang, X., Shi, Y., & Yu, B. (2022). Annual review of lysine-specific demethylase 1 (LSD1/KDM1A) inhibitors in 2021. European Journal of Medicinal Chemistry, 228, 114042. https://doi.org/10.1016/j.ejmech.2021.114042

    Article  CAS  PubMed  Google Scholar 

  114. Priedigkeit, N., Watters, R. J., Lucas, P. C., Basudan, A., Bhargava, R., Horne, W., et al. (2017). Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases. JCI. Insight, 2(17). https://doi.org/10.1172/jci.insight.95703

  115. Bado, I. L., Zhang, W., Hu, J., Xu, Z., Wang, H., Sarkar, P., et al. (2021). The bone microenvironment increases phenotypic plasticity of ER(+) breast cancer cells. Developmental Cell, 56(8), 1100–1117.e1109. https://doi.org/10.1016/j.devcel.2021.03.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang, W., Bado, I. L., Hu, J., Wan, Y. W., Wu, L., Wang, H., et al. (2021). The bone microenvironment invigorates metastatic seeds for further dissemination. Cell, 184(9), 2471–2486.e2420. https://doi.org/10.1016/j.cell.2021.03.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cote, R. J., Rosen, P. P., Lesser, M. L., Old, L. J., & Osborne, M. P. (1991). Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases. Journal of Clinical Oncology, 9(10), 1749–1756. https://doi.org/10.1200/jco.1991.9.10.1749

    Article  CAS  PubMed  Google Scholar 

  118. Cox, T. R. (2021). The matrix in cancer. Nature Reviews. Cancer, 21(4), 217–238. https://doi.org/10.1038/s41568-020-00329-7

    Article  CAS  PubMed  Google Scholar 

  119. Nemec, S., & Kilian, K. A. (2021). Materials control of the epigenetics underlying cell plasticity. Nature Reviews Materials, 6(1), 69–83. https://doi.org/10.1038/s41578-020-00238-z

    Article  CAS  Google Scholar 

  120. Lamar, J. M., Stern, P., Liu, H., Schindler, J. W., Jiang, Z. G., & Hynes, R. O. (2012). The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain. Proceedings of the National Academy of Sciences of the United States of America, 109(37), E2441–E2450. https://doi.org/10.1073/pnas.1212021109

    Article  PubMed  PubMed Central  Google Scholar 

  121. Chang, L., Azzolin, L., Di Biagio, D., Zanconato, F., Battilana, G., Lucon Xiccato, R., et al. (2018). The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. Nature, 563(7730), 265–269. https://doi.org/10.1038/s41586-018-0658-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wu, B. K., Mei, S. C., Chen, E. H., Zheng, Y., & Pan, D. (2022). YAP induces an oncogenic transcriptional program through TET1-mediated epigenetic remodeling in liver growth and tumorigenesis. Nature Genetics, 54(8), 1202–1213. https://doi.org/10.1038/s41588-022-01119-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jang, M., An, J., Oh, S. W., Lim, J. Y., Kim, J., Choi, J. K., et al. (2021). Matrix stiffness epigenetically regulates the oncogenic activation of the Yes-associated protein in gastric cancer. Nature Biomedical Engineering, 5(1), 114–123. https://doi.org/10.1038/s41551-020-00657-x

    Article  CAS  PubMed  Google Scholar 

  124. Elia, I., Doglioni, G., & Fendt, S. M. (2018). Metabolic hallmarks of metastasis formation. Trends in Cell Biology, 28(8), 673–684. https://doi.org/10.1016/j.tcb.2018.04.002

    Article  CAS  PubMed  Google Scholar 

  125. Berger, S. L., & Sassone-Corsi, P. (2016). Metabolic signaling to chromatin. Cold Spring Harbor Perspectives in Biology, 8(11). https://doi.org/10.1101/cshperspect.a019463

  126. Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S. H., et al. (2011). Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell, 19(1), 17–30. https://doi.org/10.1016/j.ccr.2010.12.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Losman, J. A., Looper, R. E., Koivunen, P., Lee, S., Schneider, R. K., McMahon, C., et al. (2013). (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science, 339(6127), 1621–1625. https://doi.org/10.1126/science.1231677

    Article  CAS  PubMed  Google Scholar 

  128. McDonald, O. G., Li, X., Saunders, T., Tryggvadottir, R., Mentch, S. J., Warmoes, M. O., et al. (2017). Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nature Genetics, 49(3), 367–376. https://doi.org/10.1038/ng.3753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Yachida, S., White, C. M., Naito, Y., Zhong, Y., Brosnan, J. A., Macgregor-Das, A. M., et al. (2012). Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clinical Cancer Research, 18(22), 6339–6347. https://doi.org/10.1158/1078-0432.Ccr-12-1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Yin, M., Guo, Y., Hu, R., Cai, W. L., Li, Y., Pei, S., et al. (2020). Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction. Nature Communications, 11(1), 1833. https://doi.org/10.1038/s41467-020-15290-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Wu, L., Cao, J., Cai, W. L., Lang, S. M., Horton, J. R., Jansen, D. J., et al. (2018). KDM5 histone demethylases repress immune response via suppression of STING. PLoS Biology, 16(8), e2006134. https://doi.org/10.1371/journal.pbio.2006134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., et al. (2018). Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell. Chemistry & Biology, 25(1), 78-87 e75. https://doi.org/10.1016/j.chembiol.2017.09.010

    Article  CAS  Google Scholar 

  133. Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001). Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proceedings of the National Academy of Sciences of the United States of America, 98(15), 8554–8559. https://doi.org/10.1073/pnas.141230798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lu, G., Middleton, R. E., Sun, H., Naniong, M., Ott, C. J., Mitsiades, C. S., et al. (2014). The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science, 343(6168), 305–309. https://doi.org/10.1126/science.1244917

    Article  CAS  PubMed  Google Scholar 

  135. Kronke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., et al. (2014). Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science, 343(6168), 301–305. https://doi.org/10.1126/science.1244851

    Article  CAS  PubMed  Google Scholar 

  136. Oser, M. G., Sabet, A. H., Gao, W., Chakraborty, A. A., Schinzel, A. C., Jennings, R. B., et al. (2019). The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis. Genes & Development, 33(23-24), 1718–1738. https://doi.org/10.1101/gad.328336.119

    Article  CAS  Google Scholar 

  137. Teng, Y. C., Lee, C. F., Li, Y. S., Chen, Y. R., Hsiao, P. W., Chan, M. Y., et al. (2013). Histone demethylase RBP2 promotes lung tumorigenesis and cancer metastasis. Cancer Research, 73(15), 4711–4721. https://doi.org/10.1158/0008-5472.Can-12-3165

    Article  CAS  PubMed  Google Scholar 

  138. Cao, J., Liu, Z., Cheung, W. K., Zhao, M., Chen, S. Y., Chan, S. W., et al. (2014). Histone demethylase RBP2 is critical for breast cancer progression and metastasis. Cell Reports, 6(5), 868–877. https://doi.org/10.1016/j.celrep.2014.02.004

    Article  CAS  PubMed  Google Scholar 

  139. Yu, X., Li, D., Kottur, J., Shen, Y., Kim, H. S., Park, K. S., et al. (2021). A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models. Science Translational Medicine, 13(613), eabj1578. https://doi.org/10.1126/scitranslmed.abj1578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Nicosia, L., Boffo, F. L., Ceccacci, E., Conforti, F., Pallavicini, I., Bedin, F., et al. (2022). Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1 oncogenic functions in AML. Oncogene, 41(6), 878–894. https://doi.org/10.1038/s41388-021-02123-7

    Article  CAS  PubMed  Google Scholar 

  141. Maiques-Diaz, A., Spencer, G. J., Lynch, J. T., Ciceri, F., Williams, E. L., Amaral, F. M. R., et al. (2018). Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia. Cell Reports, 22(13), 3641–3659. https://doi.org/10.1016/j.celrep.2018.03.012

    Article  CAS  PubMed  Google Scholar 

  142. Sheng, W., Liu, Y., Chakraborty, D., Debo, B., & Shi, Y. (2021). Simultaneous inhibition of LSD1 and TGFbeta enables eradication of poorly immunogenic tumors with anti-PD-1 treatment. Cancer Discovery, 11(8), 1970–1981. https://doi.org/10.1158/2159-8290.CD-20-0017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Bitler, B. G., Aird, K. M., Garipov, A., Li, H., Amatangelo, M., Kossenkov, A. V., et al. (2015). Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nature Medicine, 21(3), 231–238. https://doi.org/10.1038/nm.3799

    Article  CAS  PubMed  Google Scholar 

  144. Rehman, H., Chandrashekar, D. S., Balabhadrapatruni, C., Nepal, S., Balasubramanya, S. A. H., Shelton, A. K., et al. (2022). ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors. JCI. Insight, 7(16). https://doi.org/10.1172/jci.insight.155899

  145. Herberts, C., Annala, M., Sipola, J., Ng, S. W. S., Chen, X. E., Nurminen, A., et al. (2022). Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer. Nature, 608(7921), 199–208. https://doi.org/10.1038/s41586-022-04975-9

    Article  CAS  PubMed  Google Scholar 

  146. Rathert, P., Roth, M., Neumann, T., Muerdter, F., Roe, J. S., Muhar, M., et al. (2015). Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature, 525(7570), 543–547. https://doi.org/10.1038/nature14898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Shu, S., Lin, C. Y., He, H. H., Witwicki, R. M., Tabassum, D. P., Roberts, J. M., et al. (2016). Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature, 529(7586), 413–417. https://doi.org/10.1038/nature16508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Fong, C. Y., Gilan, O., Lam, E. Y., Rubin, A. F., Ftouni, S., Tyler, D., et al. (2015). BET inhibitor resistance emerges from leukaemia stem cells. Nature, 525(7570), 538–542. https://doi.org/10.1038/nature14888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Sharma, S. V., Lee, D. Y., Li, B., Quinlan, M. P., Takahashi, F., Maheswaran, S., et al. (2010). A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell, 141(1), 69–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Roesch, A., Vultur, A., Bogeski, I., Wang, H., Zimmermann, K. M., Speicher, D., et al. (2013). Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell, 23(6), 811–825. https://doi.org/10.1016/j.ccr.2013.05.003

    Article  CAS  PubMed  Google Scholar 

  151. Johansson, C., Velupillai, S., Tumber, A., Szykowska, A., Hookway, E. S., Nowak, R. P., et al. (2016). Structural analysis of human KDM5B guides histone demethylase inhibitor development. Nature Chemical Biology, 12(7), 539–545. https://doi.org/10.1038/nchembio.2087

    Article  CAS  PubMed  Google Scholar 

  152. Liu, X., Zhang, S. M., McGeary, M. K., Krykbaeva, I., Lai, L., Jansen, D. J., et al. (2019). KDM5B promotes drug resistance by regulating melanoma-propagating cell subpopulations. Molecular Cancer Therapeutics, 18(3), 706–717. https://doi.org/10.1158/1535-7163.mct-18-0395

    Article  CAS  PubMed  Google Scholar 

  153. Gale, M., Sayegh, J., Cao, J., Norcia, M., Gareiss, P., Hoyer, D., et al. (2016). Screen-identified selective inhibitor of lysine demethylase 5A blocks cancer cell growth and drug resistance. Oncotarget, 7(26), 39931-39944. https://doi.org/10.18632/oncotarget.9539.

  154. Hinohara, K., Wu, H. J., Vigneau, S., McDonald, T. O., Igarashi, K. J., Yamamoto, K. N., et al. (2018). KDM5 histone demethylase activity links cellular transcriptomic heterogeneity to therapeutic resistance. Cancer Cell. https://doi.org/10.1016/j.ccell.2018.10.014

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Acknowledgements

C.J.K. is supported by NIH grant F31CA261126. Q.Y. is supported by NIH grants P50CA121974, R01CA237586, P30CA016359, a Department of Defense Breast Cancer Research Program Breakthrough Award W81XWH-21-1-0411, and a Melanoma Research Alliance Team Science Award. D.X.N is supported by NIH grants R01CA166376, U01CA235747, P50CA196530, and P30CA016359. All figures were made with, or adapted from figures made with, BioRender.com.

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Authors and Affiliations

  1. Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA

    Carolyn J. Kravitz, Qin Yan & Don X. Nguyen

  2. Yale Cancer Center, Yale School of Medicine, New Haven, CT, 06520, USA

    Qin Yan & Don X. Nguyen

  3. Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, 06520, USA

    Qin Yan & Don X. Nguyen

  4. Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, 06520, USA

    Qin Yan

  5. Department of Internal Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, CT, 06520, USA

    Don X. Nguyen

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  1. Carolyn J. Kravitz
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  2. Qin Yan
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  3. Don X. Nguyen
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Correspondence to Qin Yan or Don X. Nguyen.

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Conflict of interest

C.J.K. reports no conflicts of interest. Q.Y. has received research funding and honorarium from AstraZeneca and is a member of Scientific Advisory Board of AccuraGen Inc. D.X.N has received research funding from AstraZeneca.

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Kravitz, C.J., Yan, Q. & Nguyen, D.X. Epigenetic markers and therapeutic targets for metastasis. Cancer Metastasis Rev 42, 427–443 (2023). https://doi.org/10.1007/s10555-023-10109-y

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