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Annual Review of Cancer Biology

Volume 7, 2023

The Role of Phase-Separated Condensates in Fusion Oncoprotein–Driven Cancers

Abstract

Fusion oncoproteins (FOs) resulting from in-frame chromosomal translocations are associated with many aggressive cancers with poor patient outcomes. Several FOs are now understood to perform their oncogenic functions within biomolecular condensates formed through liquid-liquid phase separation (LLPS). Two classes of phase-separating FOs have emerged, those that form nuclear condensates and alter chromatin biology, including gene expression, and those that form cytoplasmic condensates and promote aberrant signaling, including RAS/MAPK signaling. The amino acid sequences of the FOs within these classes display LLPS-prone intrinsically disordered regions and folded domains that synergistically interact with themselves and other biomolecules to promote condensate formation. This review summarizes the roles of LLPS in the oncogenic functions of these two FO classes, provides examples of FOs that inhibit physiological LLPS in normal cells, and discusses the sequence features commonly associated with LLPS and their enrichment in many FOs.

Keyword(s): biomolecular condensates, intrinsically disordered regions, kinase, liquid-liquid phase separation, sequence features, signaling, transcription
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/content/journals/10.1146/annurev-cancerbio-061421-122050
2023-04-11
2024-05-04
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Literature Cited

  1. Adami C. 2004. Information theory in molecular biology. Phys. Life Rev. 1:3–22
     [Google Scholar]
  2. Ahmed NS, Harrell LM, Wieland DR, Lay MA, Thompson VF, Schwartz JC. 2021. Fusion protein EWS-FLI1 is incorporated into a protein granule in cells. RNA 27:920–32
     [Google Scholar]
  3. Ahn JH, Davis ES, Daugird TA, Zhao S, Quiroga IY et al. 2021. Phase separation drives aberrant chromatin looping and cancer development. Nature 595:591–95
     [Google Scholar]
  4. Andersson AK, Ma J, Wang J, Chen X, Gedman AL et al. 2015. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nat. Genet. 47:330–37
     [Google Scholar]
  5. Baggett DW, Medyukhina A, Tripathi S, Shirnekhi HK, Wu H et al. 2022. An image analysis pipeline for quantifying the features of fluorescently-labeled biomolecular condensates in cells. Front. Bioinformat. 2: https://doi.org/10.3389/fbinf.2022.897238
    [Google Scholar]
  6. Banani SF, Lee HO, Hyman AA, Rosen MK. 2017. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18:285–98
     [Google Scholar]
  7. Boija A, Klein IA, Sabari BR, Dall'Agnese A, Coffey EL et al. 2018. Transcription factors activate genes through the phase-separation capacity of their activation domains. Cell 175:1842–55.e16
     [Google Scholar]
  8. Borcherds W, Bremer A, Borgia MB, Mittag T. 2021. How do intrinsically disordered protein regions encode a driving force for liquid-liquid phase separation?. Curr. Opin. Struct. Biol. 67:41–50
     [Google Scholar]
  9. Boulay G, Sandoval GJ, Riggi N, Iyer S, Buisson R et al. 2017. Cancer-specific retargeting of BAF complexes by a prion-like domain. Cell 171:163–78.e19
     [Google Scholar]
  10. Brangwynne CP, Eckmann CR, Courson DS, Rybarska A, Hoege C et al. 2009. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 324:1729–32
     [Google Scholar]
  11. Brien GL, Stegmaier K, Armstrong SA. 2019. Targeting chromatin complexes in fusion protein-driven malignancies. Nat. Rev. Cancer 19:255–69
     [Google Scholar]
  12. Chandra B, Michmerhuizen NL, Shirnekhi HK, Tripathi S, Pioso BJ et al. 2021. Phase separation mediates NUP98 fusion oncoprotein leukemic transformation. Cancer Discov.1152–69
     [Google Scholar]
  13. Cheng Y, Shen Z, Gao Y, Chen F, Xu H et al. 2022. Phase transition and remodeling complex assembly are important for SS18-SSX oncogenic activity in synovial sarcomas. Nat. Commun. 13:2724
     [Google Scholar]
  14. Chong S, Dugast-Darzacq C, Liu Z, Dong P, Dailey GM et al. 2018. Imaging dynamic and selective low-complexity domain interactions that control gene transcription. Science 361:eaar2555
     [Google Scholar]
  15. Clark J, Lu YJ, Sidhar SK, Parker C, Gill S et al. 1997. Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma. Oncogene 15:2233–39
     [Google Scholar]
  16. Crompton BD, Stewart C, Taylor-Weiner A, Alexe G, Kurek KC et al. 2014. The genomic landscape of pediatric Ewing sarcoma. Cancer Discov. 4:1326–41
     [Google Scholar]
  17. Davis RB, Kaur T, Moosa MM, Banerjee PR. 2021. FUS oncofusion protein condensates recruit mSWI/SNF chromatin remodeler via heterotypic interactions between prion-like domains. Protein Sci. 30:1454–66
     [Google Scholar]
  18. Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T et al. 1992. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 359:162–65
     [Google Scholar]
  19. Ditlev JA, Case LB, Rosen MK. 2018. Who's in and who's out—compositional control of biomolecular condensates. J. Mol. Biol. 430:4666–84
     [Google Scholar]
  20. Dupain C, Harttrampf AC, Urbinati G, Geoerger B, Massaad-Massade L. 2017. Relevance of fusion genes in pediatric cancers: toward precision medicine. Mol. Ther. Nucleic Acids 6:315–26
     [Google Scholar]
  21. Fawal M, Jean-Jean O, Vanzo N, Morello D. 2011. Novel mRNA-containing cytoplasmic granules in ALK-transformed cells. Mol. Biol. Cell 22:726–35
     [Google Scholar]
  22. Fox AH, Lam YW, Leung AK, Lyon CE, Andersen J et al. 2002. Paraspeckles: a novel nuclear domain. Curr. Biol. 12:13–25
     [Google Scholar]
  23. Freibaum BD, Messing J, Yang P, Kim HJ, Taylor JP. 2021. High-fidelity reconstitution of stress granules and nucleoli in mammalian cellular lysate. J. Cell Biol. 220:e202009079
     [Google Scholar]
  24. Gangwal K, Sankar S, Hollenhorst PC, Kinsey M, Haroldsen SC et al. 2008. Microsatellites as EWS/FLI response elements in Ewing's sarcoma. PNAS 105:10149–54
     [Google Scholar]
  25. Gao QS, Liang WW, Foltz SM, Mutharasu G, Jayasinghe RG et al. 2018. Driver fusions and their implications in the development and treatment of human cancers. Cell Rep. 23:227–38.e3
     [Google Scholar]
  26. Graham RP, Jin L, Knutson DL, Kloft-Nelson SM, Greipp PT et al. 2015. DNAJB1-PRKACA is specific for fibrolamellar carcinoma. Mod. Pathol. 28:822–29
     [Google Scholar]
  27. Guillon N, Tirode F, Boeva V, Zynovyev A, Barillot E, Delattre O. 2009. The oncogenic EWS-FLI1 protein binds in vivo GGAA microsatellite sequences with potential transcriptional activation function. PLOS ONE 4:e4932
     [Google Scholar]
  28. Hnisz D, Shrinivas K, Young RA, Chakraborty AK, Sharp PA. 2017. A phase separation model for transcriptional control. Cell 169:13–23
     [Google Scholar]
  29. Holehouse AS, Das RK, Ahad JN, Richardson MO, Pappu RV. 2017. CIDER: resources to analyze sequence-ensemble relationships of intrinsically disordered proteins. Biophys. J. 112:16–21
     [Google Scholar]
  30. Honeyman JN, Simon EP, Robine N, Chiaroni-Clarke R, Darcy DG et al. 2014. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343:1010–14
     [Google Scholar]
  31. Hrustanovic G, Olivas V, Pazarentzos E, Tulpule A, Asthana S et al. 2015. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK–positive lung cancer. Nat. Med. 21:1038–47
     [Google Scholar]
  32. Hyman AA, Weber CA, Julicher F. 2014. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30:39–58
     [Google Scholar]
  33. Irgen-Gioro S, Walling V, Chong S 2022. Fixation can change the appearance of phase separation in living cells. bioRxiv 2022.05.06.490956. https://doi.org/10.1101/2022.05.06.490956
  34. Jevtic Z, Matafora V, Casagrande F, Santoro F, Minucci S et al. 2022. SMARCA5 interacts with NUP98-NSD1 oncofusion protein and sustains hematopoietic cells transformation. J. Exp. Clin. Cancer Res. 41:34
     [Google Scholar]
  35. Johnson KM, Mahler NR, Saund RS, Theisen ER, Taslim C et al. 2017. Role for the EWS domain of EWS/FLI in binding GGAA-microsatellites required for Ewing sarcoma anchorage independent growth. PNAS 114:9870–75
     [Google Scholar]
  36. Kasper LH, Brindle PK, Schnabel CA, Pritchard CE, Cleary ML, van Deursen JM. 1999. CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. Mol. Cell. Biol. 19:764–76
     [Google Scholar]
  37. Kastenhuber ER, Lalazar G, Houlihan SL, Tschaharganeh DF, Baslan T et al. 2017. DNAJB1-PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. PNAS 114:13076–84
     [Google Scholar]
  38. Kato M, Han TW, Xie S, Shi K, Du X et al. 2012. Cell-free formation of RNA granules: Low complexity sequence domains form dynamic fibers within hydrogels. Cell 149:753–67
     [Google Scholar]
  39. Kauffman EC, Ricketts CJ, Rais-Bahrami S, Yang Y, Merino MJ et al. 2014. Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers. Nat. Rev. Urol. 11:465–75
     [Google Scholar]
  40. Keber FC, Nguyen T, Brangwynne CP, Wühr M. 2021. Evidence for widespread cytoplasmic structuring into mesoscopic condensates. bioRxiv 2021.12.17.473234. https://doi.org/10.1101/2021.12.17.473234
  41. Kinsey M, Smith R, Lessnick SL. 2006. NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing's sarcoma. Mol. Cancer Res. 4:851–59
     [Google Scholar]
  42. Klein IA, Boija A, Afeyan LK, Hawken SW, Fan M et al. 2020. Partitioning of cancer therapeutics in nuclear condensates. Science 368:1386–92
     [Google Scholar]
  43. Knott GJ, Bond CS, Fox AH. 2016. The DBHS proteins SFPQ, NONO and PSPC1: a multipurpose molecular scaffold. Nucleic Acids Res. 44:3989–4004
     [Google Scholar]
  44. Kuang J, Zhai Z, Li P, Shi R, Guo W et al. 2021. SS18 regulates pluripotent-somatic transition through phase separation. Nat. Commun. 12:4090
     [Google Scholar]
  45. Lancaster AK, Nutter-Upham A, Lindquist S, King OD. 2014. PLAAC: a web and command-line application to identify proteins with prion-like amino acid composition. Bioinformatics 30:2501–2
     [Google Scholar]
  46. Latysheva NS, Oates ME, Maddox L, Flock T, Gough J et al. 2016. Molecular principles of gene fusion mediated rewiring of protein interaction networks in cancer. Mol. Cell 63:579–92
     [Google Scholar]
  47. Lin CC, Suen KM, Jeffrey PA, Wieteska L, Lidster JA et al. 2022. Receptor tyrosine kinases regulate signal transduction through a liquid-liquid phase separated state. Mol. Cell 82:1089–106.e12
     [Google Scholar]
  48. Lobato MN, Metzler M, Drynan L, Forster A, Pannell R, Rabbitts TH. 2008. Modeling chromosomal translocations using conditional alleles to recapitulate initiating events in human leukemias. J. Natl. Cancer Inst. Monogr. 2008:3958–63
     [Google Scholar]
  49. Lu S, Wang J, Chitsaz F, Derbyshire MK, Geer RC et al. 2020. CDD/SPARCLE: the conserved domain database in 2020. Nucleic Acids Res. 48:D265–68
     [Google Scholar]
  50. Martina JA, Diab HI, Lishu L, Jeong AL, Patange S et al. 2014. The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Sci. Signal. 7:ra9
     [Google Scholar]
  51. Mathieu C, Pappu RV, Taylor JP. 2020. Beyond aggregation: pathological phase transitions in neurodegenerative disease. Science 370:56–60
     [Google Scholar]
  52. May WA, Gishizky ML, Lessnick SL, Lunsford LB, Lewis BC et al. 1993. Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation. PNAS 90:5752–56
     [Google Scholar]
  53. McNeer NA, Philip J, Geiger H, Ries RE, Lavallée VP et al. 2019. Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia. Leukemia 33:1934–43
     [Google Scholar]
  54. McSwiggen DT, Hansen AS, Teves SS, Marie-Nelly H, Hao Y et al. 2019a. Evidence for DNA-mediated nuclear compartmentalization distinct from phase separation. eLife 8:e47098
     [Google Scholar]
  55. McSwiggen DT, Mir M, Darzacq X, Tjian R. 2019b. Evaluating phase separation in live cells: diagnosis, caveats, and functional consequences. Genes Dev. 33:1619–34
     [Google Scholar]
  56. Mertens F, Antonescu CR, Mitelman F. 2016. Gene fusions in soft tissue tumors: recurrent and overlapping pathogenetic themes. Genes Chromosom. Cancer 55:291–310
     [Google Scholar]
  57. Meszaros B, Erdos G, Dosztanyi Z. 2018. IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding. Nucleic Acids Res. 46:W329–37
     [Google Scholar]
  58. Michmerhuizen NL, Klco JM, Mullighan CG. 2020. Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies. Blood 136:2275–89
     [Google Scholar]
  59. Mitrea DM, Chandra B, Ferrolino MC, Gibbs EB, Tolbert M et al. 2018. Methods for physical characterization of phase-separated bodies and membrane-less organelles. J. Mol. Biol. 430:4773–805
     [Google Scholar]
  60. Nagai M, Tanaka S, Tsuda M, Endo S, Kato H et al. 2001. Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2α. PNAS 98:3843–48
     [Google Scholar]
  61. Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K et al. 1996. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat. Genet. 12:154–58
     [Google Scholar]
  62. Nowell P, Hungerford D. 1960. A minute chromosome in human chronic granulocytic leukemia. Science 132:1497 (Abstr.)
     [Google Scholar]
  63. Oka M, Mura S, Yamada K, Sangel P, Hirata S et al. 2016. Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes. eLife 5:e09540
     [Google Scholar]
  64. Owen I, Yee D, Wyne H, Perdikari TM, Johnson V et al. 2021. The oncogenic transcription factor FUS-CHOP can undergo nuclear liquid-liquid phase separation. J. Cell Sci. 134:17jcs258578
     [Google Scholar]
  65. Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M et al. 2015. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162:1066–77
     [Google Scholar]
  66. Patel M, Simon JM, Iglesia MD, Wu SB, McFadden AW et al. 2012. Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription. Genome Res. 22:259–70
     [Google Scholar]
  67. Peeples W, Rosen MK. 2021. Mechanistic dissection of increased enzymatic rate in a phase-separated compartment. Nat. Chem. Biol. 17:693–702
     [Google Scholar]
  68. Perry JA, Seong BKA, Stegmaier K. 2019. Biology and therapy of dominant fusion oncoproteins involving transcription factor and chromatin regulators in sarcomas. Annu. Rev. Cancer Biol. 3:299–321
     [Google Scholar]
  69. Pritchard CE, Fornerod M, Kasper LH, van Deursen JM. 1999. RAE1 is a shuttling mRNA export factor that binds to a GLEBS-like NUP98 motif at the nuclear pore complex through multiple domains. J. Cell Biol. 145:237–54
     [Google Scholar]
  70. Qin Z, Sun H, Yue M, Pan X, Chen L et al. 2021. Phase separation of EML4–ALK in firing downstream signaling and promoting lung tumorigenesis. Cell Discov. 7:33
     [Google Scholar]
  71. Radu A, Moore MS, Blobel G. 1995. The peptide repeat domain of nucleoporin Nup98 functions as a docking site in transport across the nuclear pore complex. Cell 81:215–22
     [Google Scholar]
  72. Riback JA, Zhu L, Ferrolino MC, Tolbert M, Mitrea DM et al. 2020. Composition-dependent thermodynamics of intracellular phase separation. Nature 581:209–14
     [Google Scholar]
  73. Richards MW, O'Regan L, Roth D, Montgomery JM, Straube A et al. 2015. Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain. Biochem. J. 467:529–36
     [Google Scholar]
  74. Riggi N, Knoechel B, Gillespie SM, Rheinbay E, Boulay G et al. 2014. EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma. Cancer Cell 26:668–81
     [Google Scholar]
  75. Sabari BR, Dall'Agnese A, Boija A, Klein IA, Coffey EL et al. 2018. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361:6400aar3958
     [Google Scholar]
  76. Salokas K, Weldatsadik RG, Varjosalo M. 2020. Human transcription factor and protein kinase gene fusions in human cancer. Sci. Rep. 10:14169
     [Google Scholar]
  77. Sampson J, Richards MW, Choi J, Fry AM, Bayliss R. 2021. Phase-separated foci of EML4-ALK facilitate signalling and depend upon an active kinase conformation. EMBO Rep. 22:e53693
     [Google Scholar]
  78. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M et al. 2009. A gene network regulating lysosomal biogenesis and function. Science 325:473–77
     [Google Scholar]
  79. Shao X, Chen Y, Xu A, Xiang D, Wang W et al. 2022. Deneddylation of PML/RARα reconstructs functional PML nuclear bodies via orchestrating phase separation to eradicate APL. Cell Death Differ. 29:81654–68
     [Google Scholar]
  80. Shimobayashi SF, Ronceray P, Sanders DW, Haataja MP, Brangwynne CP. 2021. Nucleation landscape of biomolecular condensates. Nature 599:503–6
     [Google Scholar]
  81. Shin Y, Brangwynne CP. 2017. Liquid phase condensation in cell physiology and disease. Science 357:6357aaf4382
     [Google Scholar]
  82. Su X, Ditlev JA, Hui E, Xing W, Banjade S et al. 2016. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352:595–99
     [Google Scholar]
  83. Terlecki-Zaniewicz S, Humer T, Eder T, Schmoellerl J, Heyes E et al. 2021. Biomolecular condensation of NUP98 fusion proteins drives leukemogenic gene expression. Nat. Struct. Mol. Biol. 28:190–201
     [Google Scholar]
  84. Thelin-Jarnum S, Goransson M, Burguete AS, Olofsson A, Aman P. 2002. The myxoid liposarcoma specific TLS-CHOP fusion protein localizes to nuclear structures distinct from PML nuclear bodies. Int. J. Cancer 97:446–50
     [Google Scholar]
  85. Torrisi M, Kaleel M, Pollastri G. 2019. Deeper profiles and cascaded recurrent and convolutional neural networks for state-of-the-art protein secondary structure prediction. Sci. Rep. 9:12374
     [Google Scholar]
  86. Tulpule A, Guan J, Neel DS, Allegakoen HR, Lin YP et al. 2021. Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules. Cell 184:2649–64.e18
     [Google Scholar]
  87. Vernon RM, Chong PA, Tsang B, Kim TH, Bah A et al. 2018. Pi-Pi contacts are an overlooked protein feature relevant to phase separation. eLife 7:e31486
     [Google Scholar]
  88. Wang B, Gan W, Han X, Liu N, Ma T, Li D 2021. The positive regulation loop between NRF1 and NONO-TFE3 fusion promotes phase separation and aggregation of NONO-TFE3 in NONO-TFE3 tRCC. Int. J. Biol. Macromol. 176:437–47
     [Google Scholar]
  89. Wang J, Choi JM, Holehouse AS, Lee HO, Zhang X et al. 2018. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell 174:688–99.e16
     [Google Scholar]
  90. Wei MT, Elbaum-Garfinkle S, Holehouse AS, Chen CC-H, Feric M et al. 2017. Phase behaviour of disordered proteins underlying low density and high permeability of liquid organelles. Nat. Chem. 9:1118–25
     [Google Scholar]
  91. Xia QY, Wang Z, Chen N, Gan HL, Teng XD et al. 2017. Xp11.2 translocation renal cell carcinoma with NONO-TFE3 gene fusion: morphology, prognosis, and potential pitfall in detecting TFE3 gene rearrangement. Mod. Pathol. 30:416–26
     [Google Scholar]
  92. Xu H, Valerio DG, Eisold ME, Sinha A, Koche RP et al. 2016. NUP98 fusion proteins interact with the NSL and MLL1 complexes to drive leukemogenesis. Cancer Cell 30:863–78
     [Google Scholar]
  93. Yin X, Wang B, Gan W, Zhuang W, Xiang Z et al. 2019. TFE3 fusions escape from controlling of mTOR signaling pathway and accumulate in the nucleus promoting genes expression in Xp11.2 translocation renal cell carcinomas. J. Exp. Clin. Cancer Res. 38:119
     [Google Scholar]
  94. Zhang JZ, Lu TW, Stolerman LM, Tenner B, Yang JR et al. 2020. Phase separation of a PKA regulatory subunit controls cAMP compartmentation and oncogenic signaling. Cell 182:1531–44.e15
     [Google Scholar]
  95. Zuo L, Zhang G, Massett M, Cheng J, Guo Z et al. 2021. Loci-specific phase separation of FET fusion oncoproteins promotes gene transcription. Nat. Commun. 12:1491
     [Google Scholar]
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The Role of Phase-Separated Condensates in Fusion Oncoprotein–Driven Cancers
Annual Review of Cancer Biology 7, 73 (2023); https://doi.org/10.1146/annurev-cancerbio-061421-122050
/content/journals/10.1146/annurev-cancerbio-061421-122050
/content/journals/10.1146/annurev-cancerbio-061421-122050
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