A transcriptome-based signature of pathological angiogenesis predicts breast cancer patient survival

Autoři: Rodrigo Guarischi-Sousa aff001;  Jhonatas S. Monteiro aff001;  Lilian C. Alecrim aff001;  Jussara S. Michaloski aff001;  Laura B. Cardeal aff001;  Elisa N. Ferreira aff003;  Dirce M. Carraro aff003;  Diana N. Nunes aff003;  Emmanuel Dias-Neto aff003;  Jüri Reimand aff002;  Paul C. Boutros aff006;  João C. Setubal aff001;  Ricardo J. Giordano aff001
Působiště autorů: Biochemistry Department, Institute of Chemistry, University of São Paulo, São Paulo, Brazil aff001;  Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada aff002;  International Research Center (CIPE) A.C. Camargo Cancer Center, São Paulo, SP, Brazil aff003;  Laboratory of Neurosciences (LIM27), Institute & Department of Psychiatry, University of São Paulo, São Paulo, Brazil aff004;  Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada aff005;  Department of Human Genetics, University of California Los Angeles (UCLA), Los Angeles, CA, United States of America aff006
Vyšlo v časopise: A transcriptome-based signature of pathological angiogenesis predicts breast cancer patient survival. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008482
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008482


The specific genes and molecules that drive physiological angiogenesis differ from those involved in pathological angiogenesis, suggesting distinct mechanisms for these seemingly related processes. Unveiling genes and pathways preferentially associated with pathologic angiogenesis is key to understanding its mechanisms, thereby facilitating development of novel approaches to managing angiogenesis-dependent diseases. To better understand these different processes, we elucidated the transcriptome of the mouse retina in the well-accepted oxygen-induced retinopathy (OIR) model of pathological angiogenesis. We identified 153 genes changed between normal and OIR retinas, which represent a molecular signature relevant to other angiogenesis-dependent processes such as cancer. These genes robustly predict the survival of breast cancer patients, which was validated in an independent 1,000-patient test cohort (40% difference in 15-year survival; p = 2.56 x 10−21). These results suggest that the OIR model reveals key genes involved in pathological angiogenesis, and these may find important applications in stratifying tumors for treatment intensification or for angiogenesis-targeted therapies.

Klíčová slova:

Angiogenesis – Breast cancer – Gene expression – Medical hypoxia – Retina – RNA sequencing – Transcriptome analysis – Oxygen-induced retinopathy


1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971; 285:1182–6. doi: 10.1056/NEJM197111182852108 4938153

2. Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007; 6:273–86. doi: 10.1038/nrd2115 17396134

3. Cao Y, Arbiser J, D’Amato RJ, D’Amore PA, Ingber DE, Kerbel R, Klagsbrun M, Lim S, Moses MA, Zetter B, Dvorak H, Langer R. Forty-year journey of angiogenesis translational research. Sci Transl Med. 2011; 3:114rv3. doi: 10.1126/scitranslmed.3003149 22190240

4. Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov. 2016; 15:385–403. doi: 10.1038/nrd.2015.17 26775688

5. Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014; 26:605–22. doi: 10.1016/j.ccell.2014.10.006 25517747

6. Karaman S, Leppänen VM, Alitalo K. Vascular endothelial growth factor signaling in development and disease. Development. 2018; 145, pii:dev151019.

7. Bahrami B, Zhu M, Hong T, Chang A. Diabetic macular oedema: pathophysiology, management challenges and treatment resistance. Diabetologia. 2016; 59:1594–608. doi: 10.1007/s00125-016-3974-8 27179659

8. Montero AJ, Escobar M, Lopes G, Glück S, Vogel C. Bevacizumab in the treatment of metastatic breast cancer: friend or foe? Curr. Oncol. Rep. 2012; 14:1–11. doi: 10.1007/s11912-011-0202-z 22012632

9. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646–74. doi: 10.1016/j.cell.2011.02.013 21376230

10. Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, Molina DA, Salcedo R, Back T, Cramer S, Dai RM, Kiu H, Cardone M, Naik S, Patri AK, Wang E, Marincola FM, Frank KM, Belkaid Y, Trinchieri G, Goldszmid RS. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013; 342:967–70. doi: 10.1126/science.1240527 24264989

11. Mlecnik B, Bindea G, Kirilovsky A, Angell HK, Obenauf AC, Tosolini M, Church SE, Maby P, Vasaturo A, Angelova M, Fredriksen T, Mauger S, Waldner M, Berger A, Speicher MR, Pagès F, Valge-Archer V, Galon J. The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med. 8:327ra26 (2016). doi: 10.1126/scitranslmed.aad6352 26912905

12. Espiritu SMG, Liu LY, Rubanova Y, Bhandari V, Holgersen EM, Szyca LM, Fox NS, Chua MLK, Yamaguchi TN, Heisler LE, Livingstone J, Wintersinger J, Yousif F, Lalonde E, Rouette A, Salcedo A, Houlahan KE, Li CH, Huang V, Fraser M, van der Kwast T, Morris QD, Bristow RG, Boutros PC. The evolutionary landscape of localized prostate cancers drives clinical aggression. Cell 2018; 173:1003–1013. doi: 10.1016/j.cell.2018.03.029 29681457

13. Lahdenranta J, Pasqualini R, Schlingemann RO, Hagedorn M, Stallcup WB, Bucana CD, Sidman RL, Arap W. An anti-angiogenic state in mice and humans with retinal photoreceptor cell degeneration. Proc Natl Acad Sci U. S. A. 2001; 98:10368–73. doi: 10.1073/pnas.181329198 11526242

14. Giordano RJ, Cardó-Vila M, Salameh A, Anobom CD, Zeitlin BD, Hawke DH, Valente AP, Almeida FC, Nör JE, Sidman RL, Pasqualini R, Arap W. From combinatorial peptide selection to drug prototype (I): targeting the vascular endothelial growth factor receptor pathway. Proc Natl Acad Sci U. S. A. 2010; 107:5112–7. doi: 10.1073/pnas.0915141107 20190181

15. Cloutier F, Lawrence M, Goody R, Lamoureux S, Al-Mahmood S, Colin S, Ferry A, Conduzorgues JP, Hadri A, Cursiefen C, Udaondo P, Viaud E, Thorin E, Chemtob S. Antiangiogenic activity of aganirsen in nonhuman primate and rodent models of retinal neovascular disease after topical administration. Invest Ophthalmol Vis Sci. 2012; 53:1195–203. doi: 10.1167/iovs.11-9064 22323484

16. Sidman RL, Li J, Lawrence M, Hu W, Musso GF, Giordano RJ, Cardó-Vila M, Pasqualini R, Arap W. The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease. Sci Transl Med. 2015; 7:309ra165. doi: 10.1126/scitranslmed.aac4882 26468327

17. Nunes DN, Dias-Neto E, Cardó-Vila M, Edwards JK, Dobroff AS, Giordano RJ, Mandelin J, Brentani HP, Hasselgren C, Yao VJ, Marchiò S, Pereira CA, Passetti F, Calin GA, Sidman RL, Arap W, Pasqualini R. Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch. Proc Natl Acad Sci U. S. A. 2015; 112:3770–5. doi: 10.1073/pnas.1500008112 25775553

18. Michaloski JS, Redondo AR, Magalhães LS, Cambui CC, Giordano RJ. Discovery of pan-VEGF inhibitory peptides directed to the extracellular ligand-binding domains of the VEGF receptors. Sci Adv. 2016; 2:e1600611. doi: 10.1126/sciadv.1600611 27819042

19. Smith LE, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R, D’Amore PA. Oxygen-induced retinopathy in the mouse. Invest. Ophthalmol. Vis. Sci. 1994; 35:101–111. 7507904

20. Stahl A, Connor KM, Sapieha P, Chen J, Dennison RJ, Krah NM, Seaward MR, Willett KL, Aderman CM, Guerin KI, Hua J, Löfqvist C, Hellström A, Smith LE. The mouse retina as an angiogenesis model. Invest Ophthalmol Vis Sci. 2010; 51:2813–26. doi: 10.1167/iovs.10-5176 20484600

21. Hellström A, Smith LE, Dammann O. Dammann, Retinopathy of prematurity. Lancet. 2013; 382:1445–57. doi: 10.1016/S0140-6736(13)60178-6 23782686

22. Scott A, Fruttiger M. Oxygen-induced retinopathy: a model for vascular pathology in the retina. Eye (London) 2010; 24:416–21.

23. Masland RH. The neuronal organization of the retina. Neuron. 2012; 76:266–80. doi: 10.1016/j.neuron.2012.10.002 23083731

24. Carmeliet P. Blood vessels and nerves: common signals, pathways and diseases. 2003; Nat Rev Genet. 4:710–20. doi: 10.1038/nrg1158 12951572

25. Licht T, Keshet E. Delineating multiple functions of VEGF-A in the adult brain. Cell Mol. Life Sci. 2013; 70:1727–37. doi: 10.1007/s00018-013-1280-x 23475068

26. Boutros PC, Lau SK, Pintilie M, Liu N, Shepherd FA, Der SD, Tsao MS, Penn LZ, Jurisica I. Prognostic gene signatures for non-small-cell lung cancer. Proc Natl Acad Sci U S A. 2009;106:2824–8. doi: 10.1073/pnas.0809444106 19196983

27. Starmans MH, Chu KC, Haider S, Nguyen F, Seigneuric R, Magagnin MG, Koritzinsky M, Kasprzyk A, Boutros PC, Wouters BG, Lambin P. The prognostic value of temporal in vitro and in vivo derived hypoxia gene-expression signatures in breast cancer. Radiother Oncol. 2012; 102:436–43. doi: 10.1016/j.radonc.2012.02.002 22356756

28. Stefansson IM, Raeder M, Wik E, Mannelqvist M, Kusonmano K, Knutsvik G, Haldorsen I, Trovik J, Øyan AM, Kalland KH, Staff AC, Salvesen HB, Akslen LA. Increased angiogenesis is associated with a 32-gene expression signature and 6p21 amplification in aggressive endometrial cancer. Oncotarget. 2015; 6:10634–45. doi: 10.18632/oncotarget.3521 25860936

29. Langlois B, Saupe F, Rupp T, Arnold C, van der Heyden M, Orend G, Hussenet T. AngioMatrix, a signature of the tumor angiogenic switch-specific matrisome, correlates with poor prognosis for glioma and colorectal cancer patients. Oncotarget. 2014; 5:10529–45. doi: 10.18632/oncotarget.2470 25301723

30. Sanmartín E, Sirera R, Usó M, Blasco A, Gallach S, Figueroa S, Martínez N, Hernando C, Honguero A, Martorell M, Guijarro R, Rosell R, Jantus-Lewintre E, Camps C. A gene signature combining the tissue expression of three angiogenic factors is a prognostic marker in early-stage non-small cell lung cancer. Ann Surg Oncol. 2014; 21:612–20. doi: 10.1245/s10434-013-3330-x 24145997

31. Pinato DJ, Tan TM, Toussi ST, Ramachandran R, Martin N, Meeran K, Ngo N, Dina R, Sharma R. An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes. Br J Cancer 2014; 110:115–122. doi: 10.1038/bjc.2013.682 24231952

32. Khong TL, Thairu N, Larsen H, Dawson PM, Kiriakidis S, Paleolog EM. Identification of the angiogenic gene signature induced by EGF and hypoxia in colorectal cancer. BMC Cancer. 2013; 13:518. doi: 10.1186/1471-2407-13-518 24180698

33. Masiero M, Simões FC, Han HD, Snell C, Peterkin T, Bridges E, Mangala LS, Wu SY, Pradeep S, Li D, Han C, Dalton H, Lopez-Berestein G, Tuynman JB, Mortensen N, Li JL, Patient R, Sood AK, Banham AH, Harris AL, Buffa FM. A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis. Cancer Cell. 2013; 24:229–41. doi: 10.1016/j.ccr.2013.06.004 23871637

34. Bentink S, Haibe-Kains B, Risch T, Fan JB, Hirsch MS, Holton K, Rubio R, April C, Chen J, Wickham-Garcia E, Liu J, Culhane A, Drapkin R, Quackenbush J, Matulonis UA. Angiogenic mRNA and microRNA gene expression signature predicts a novel subtype of serous ovarian cancer. PLoS One. 2012; 7:e30269. doi: 10.1371/journal.pone.0030269 22348002

35. Mendiola M, Barriuso J, Redondo A, Mariño-Enríquez A, Madero R, Espinosa E, Vara JA, Sánchez-Navarro I, Hernández-Cortes G, Zamora P, Pérez-Fernández E, Miguel-Martín M, Suárez A, Palacios J, González-Barón M, Hardisson D. Angiogenesis-related gene expression profile with independent prognostic value in advanced ovarian carcinoma. PLoS One. 2008; 3:e4051. doi: 10.1371/journal.pone.0004051 19112514

36. Hu J, Bianchi F, Ferguson M, Cesario A, Margaritora S, Granone P, Goldstraw P, Tetlow M, Ratcliffe C, Nicholson AG, Harris A, Gatter K, Pezzella F. Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer. Oncogene. 2005; 24:1212–9. doi: 10.1038/sj.onc.1208242 15592519

37. Sørensen BS, Toustrup K, Horsman MR, Overgaard J, Alsner J. Identifying pH independent hypoxia induced genes in human squamous cell carcinomas in vitro. Acta Oncol. 2010; 49(7):895–905. doi: 10.3109/02841861003614343 20429727

38. Buffa FM, Harris AL, West CM, Miller CJ. Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br J Cancer. 2010; 102:428–35. doi: 10.1038/sj.bjc.6605450 20087356

39. Seigneuric R, Starmans MH, Fung G, Krishnapuram B, Nuyten DS, van Erk A, Magagnin MG, Rouschop KM, Krishnan S, Rao RB, Evelo CT, Begg AC, Wouters BG, Lambin P. Impact of supervised gene signatures of early hypoxia on patient survival. Radiother Oncol. 2007; 83:374–82. doi: 10.1016/j.radonc.2007.05.002 17532074

40. Winter SC, Buffa FM, Silva P, Miller C, Valentine HR, Turley H, Shah KA, Cox GJ, Corbridge RJ, Homer JJ, Musgrove B, Slevin N, Sloan P, Price P, West CM, Harris AL. Relation of a hypoxia metagene derived from head and neck cancer to prognosis of multiple cancers. Cancer Res. 2007; 67:3441–9. doi: 10.1158/0008-5472.CAN-06-3322 17409455

41. Elvidge GP, Glenny L, Appelhoff RJ, Ratcliffe PJ, Ragoussis J, Gleadle JM. Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways. J. Biol. Chem. 2006; 281:15215–26. doi: 10.1074/jbc.M511408200 16565084

42. Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A, Wang Y, Kristensen GB, Helland A, Børresen-Dale AL, Giaccia A, Longaker MT, Hastie T, Yang GP, van de Vijver MJ, Brown PO. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med. 2006; 3:e47. doi: 10.1371/journal.pmed.0030047 16417408

43. Hu Z, Fan C, Livasy C, He X, Oh DS, Ewend MG, Carey LA, Subramanian S, West R, Ikpatt F, Olopade OI, van de Rijn M, Perou CM. A compact VEGF signature associated with distant metastases and poor outcomes. BMC Med. 2009; 7:9. doi: 10.1186/1741-7015-7-9 19291283

44. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Gräf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S; METABRIC Group, Langerød A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Børresen-Dale AL, Brenton JD, Tavaré S, Caldas C, Aparicio S. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012; 486:346–52. doi: 10.1038/nature10983 22522925

45. Venet D, Dumont JE, Detours V. Most random gene expression signatures are significantly associated with breast cancer outcome. PLoS Comput Biol. 2011; 7:e1002240. doi: 10.1371/journal.pcbi.1002240 22028643

46. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature. 2000; 406:747–52. doi: 10.1038/35021093 10963602

47. Nowak-Sliwinska P, Alitalo K, Allen E, Anisimov A, Aplin AC, Auerbach R, Augustin HG, Bates DO, van Beijnum JR, Bender RHF, Bergers G, Bikfalvi A, Bischoff J, Böck BC, Brooks PC, Bussolino F, Cakir B, Carmeliet P, Castranova D, Cimpean AM, Cleaver O, Coukos G, Davis GE, De Palma M, Dimberg A, Dings RPM, Djonov V, Dudley AC, Dufton NP, Fendt SM, Ferrara N, Fruttiger M, Fukumura D, Ghesquière B, Gong Y, Griffin RJ, Harris AL, Hughes CCW, Hultgren NW, Iruela-Arispe ML, Irving M, Jain RK, Kalluri R, Kalucka J, Kerbel RS, Kitajewski J, Klaassen I, Kleinmann HK, Koolwijk P, Kuczynski E, Kwak BR, Marien K, Melero-Martin JM, Munn LL, Nicosia RF, Noel A, Nurro J, Olsson AK, Petrova TV, Pietras K, Pili R, Pollard JW, Post MJ, Quax PHA, Rabinovich GA, Raica M, Randi AM, Ribatti D, Ruegg C, Schlingemann RO, Schulte-Merker S, Smith LEH, Song JW, Stacker SA, Stalin J, Stratman AN, Van de Velde M, van Hinsbergh VWM, Vermeulen PB, Waltenberger J, Weinstein BM, Xin H, Yetkin-Arik B, Yla-Herttuala S, Yoder MC, Griffioen AW. Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis. 2018; doi: 10.1007/s10456-018-9613-x [Epub ahead of print] 29766399

48. Gao SP, Sun HF, Li LD, Fu WY, Jin W. UHRF1 promotes breast cancer progression by suppressing KLF17 expression by hypermethylating its promoter. Am J Cancer Res. 2017 Jul 1;7(7):1554–1565. eCollection 2017. 28744404

49. Achour M, Jacq X, Rondé P, Alhosin M, Charlot C, Chataigneau T, Jeanblanc M, Macaluso M, Giordano A, Hughes AD, Schini-Kerth VB, Bronner C. The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. Oncogene. 2008 Apr 3;27(15):2187–97. Epub 2007 Oct 15. doi: 10.1038/sj.onc.1210855 17934516

50. Yang H, Liu C, Zhou RM, Yao J, Li XM, Shen Y, Cheng H, Yuan J, Yan B, Jiang Q. Piezo2 protein: A novel regulator of tumor angiogenesis and hyperpermeability. Oncotarget. 2016 Jul 12;7(28):44630–44643. doi: 10.18632/oncotarget.10134 27329839

51. Takayama Y, Hattori N, Hamada H, Masuda T, Omori K, Akita S, Iwamoto H, Fujitaka K, Kohno N. Inhibition of PAI-1 Limits Tumor Angiogenesis Regardless of Angiogenic Stimuli in Malignant Pleural Mesothelioma. Cancer Res. 2016 Jun 1;76(11):3285–94. doi: 10.1158/0008-5472.CAN-15-1796 Epub 2016 Apr 13. 27197170

52. Peters I, Dubrowinskaja N, Abbas M, Seidel C, Kogosov M, Scherer R, Gebauer K, Merseburger AS, Kuczyk MA, Grünwald V, Serth J. DNA methylation biomarkers predict progression-free and overall survival of metastatic renal cell cancer (mRCC) treated with antiangiogenic therapies. PLoS One. 2014 Mar 14;9(3):e91440. doi: 10.1371/journal.pone.0091440 eCollection 2014. 24633192

53. Schwartzberg LS, Tauer KW, Hermann RC, Makari-Judson G, Isaacs C, Beck JT, Kaklamani V, Stepanski EJ, Rugo HS, Wang W, Bell-McGuinn K, Kirshner JJ, Eisenberg P, Emanuelson R, Keaton M, Levine E, Medgyesy DC, Qamar R, Starr A, Ro SK, Lokker NA, Hudis CA. Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab. Clin. Can. Res. 2013;19: 2745–54.

54. Dirix LY, Reynolds AR. Bevacizumab beyond progression in breast cancer. Lancet Oncol. 2014;15:1190–1. doi: 10.1016/S1470-2045(14)70454-1 25273341

55. Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, Mariani P, Andre F, Chan A, Lipatov O, Chan S, Wardley A, Greil R, Moore N, Prot S, Pallaud C, Semiglazov V. AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J. Clin. Oncol. 2013; 31:1719–25. doi: 10.1200/JCO.2012.44.7912 23569311

56. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001;21(12):3995–4004. doi: 10.1128/MCB.21.12.3995-4004.2001 11359907

57. Alameddine RS, Otrock ZK, Awada A, Shamseddine A. Crosstalk between HER2 signaling and angiogenesis in breast cancer: molecular basis, clinical applications and challenges. Curr Opin Oncol. 2013; 25(3):313–24. doi: 10.1097/CCO.0b013e32835ff362 23518595

58. Bhandari V, Boutros PC. Comparing continuous and discrete analyses of breast cancer survival information. Genomics. 2016; 108:78–83. doi: 10.1016/j.ygeno.2016.06.002 27311755

59. P’ng C., Green J., Chong L.C., Waggott D., Prokopec S.D., Shamsi M., Nguyen F., Mak D.Y.F., Lam F., Albuquerque M.A., Wu Y., Jung E.H., Starmans M.H.W., Chan-Seng-Yue M.A., Yao C.Q., Liang B., Lalonde E., Haider S., Simone N.A., Sendorek D., Chu K.C., Moon N.C., Fox N.S., Grzadkowski M.R., Harding N.J., Fung C., Murdoch A.R., Houlahan K.E., Wang J., Garcia D.R., Borja R., Sun R.X., Lin X., Chen G.M., Lu A., Shiah Y., Zia A., Kearns R., Boutros P. BPG: Seamless, Automated and Interactive Visualization of Scientific Data. doi: 10.1186/s12859-019-2610-2 30665349

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