Joseph Costello PhD

Joe Costello, PhD

Professor in Residence of Neurological Surgery

Karen Osney Brownstein Endowed Chair in Molecular Neuro-Oncology

Principal Investigator, Brain Tumor Center

Director, NIH-sponsored Training Grant in Translational Brain Tumor Research

Costello Lab Website ►

The Costello laboratory is composed of cell, molecular and computational biologists working alongside clinician-scientists. Our goal is to understand the full evolutionary history of human brain tumors, from the first mutation and epimutation through clonal selection and tumor recurrence. We use next-generation sequencing to discover patterns and interdependencies of genetic mutations, epigenetic alterations and gene expression. We also investigate the influence of selective pressures such as temozolomide on tumor evolution. Current projects incorporate MRI guided tumor biopsies and treatment data with longitudinal genomics to allow the reconstruction of tumor evolution in the context of the human tumor in vivo. We recently discovered the transcription factor that is recruited to the TERT promoter mutation across cancer types, and are studying the signaling pathways that regulate GABP. We are also pursuing studies to reverse tumor cell immortality which is initiated by the mutation in the TERT promoter.TERT promoter mutation is the most common point mutation in GBM and oligodendroglioma, and the third most common mutation overall in human cancer.

Education, Training, and Previous Positions

1994: PhD, Loyola University
1994-1999: Postdoctoral Fellow, Ludwig Institute for Cancer Research, San Diego
2000-Present: Department of Neurological Surgery, UCSF

Selected Honors and Awards

2005: Karen Osney Brownstein Endowed Chair in Molecular Neuro-Oncology
2010: Outstanding Research Achievement Award, by Nature Biotechnology
2012: Keynote Lecture, European Association for Neuro-Oncology Annual Meeting
2013: Keynote Lecture, Inaugural Clinical Epigenomics Conference
2013: Distinguished Lecture, DKFZ, Heidelberg
2013: Chair, Gordon Conference on Genetics and Epigenetics
2014: Keynote Lecture, Medulloblastoma in the Mountains
2014: Keynote Lecture, ISCO meeting, Cancer Genome: From Structure to Function
2014: Keynote Lecture, EMBO Workshop on Epigenetic Plasticity, Portugal
2014: Oncology Society Lecture, Mayo Clinic
2015: AIRC Lecture, 11th World Conference on The Future of Science
2016: Keynote Lecture, Stanford University Cancer Center Annual Retreat
2016: Keynote Plenary Lecture, Society for Neuro-Oncology Annual Meeting

Selected Recent Publications

Choi S, Yu Y, Grimmer MR, Wahl M, Chang SM, Costello JF. Temozolomide-associated Hypermutation in Gliomas. Neuro Oncol. 2018 Feb 14. doi: 10.1093/neuonc/noy016. [Epub ahead of print] PubMed PMID: 29452419.

Aldape K, Amin SB, Ashley DM, Barnholtz-Sloan JS, Bates AJ, Beroukhim R, Bock C, Brat DJ, Claus EB, Costello JF, de Groot JF, Finocchiaro G, French PJ, Gan HK, Griffith B, Herold-Mende CC, Horbinski C, Iavarone A, Kalkanis SN, Karabatsou K, Kim H, Kouwenhoven MCM, McDonald KL, Miletic H, Nam DH, Ng HK, Niclou SP, Noushmehr H, Ormond R, Poisson LM, Reifenberger G, Roncaroli F, Sa JK, Sillevis Smitt PAE, Smits M, Souza CF, Tabatabai G, Van Meir EG, Verhaak RGW, Watts C, Wesseling P, Woehrer A, Yung WKA, Jungk C, Hau AC, van Dyck E, Westerman BA, Yin J, Abiola O, Zeps N, Grimmond S, Buckland M, Khasraw M, Sulman EP, Muscat AM, Stead L; GLASS Consortium. Glioma Through the Looking GLASS: Molecular Evolution of Diffuse Gliomas and the Glioma Longitudinal AnalySiS Consortium. Neuro Oncol. 2018 Feb 8. doi: 10.1093/neuonc/noy020. [Epub ahead of print] PubMed PMID: 29432615.

Hayes J, Yu Y, Jalbert LE, Mazor T, Jones LE, Wood MD, Walsh KM, Bengtsson H, Hong C, Oberndorfer S, Roetzer T, Smirnov IV, Clarke JL, Aghi MK, Chang SM, Nelson SJ, Woehrer A, Phillips JJ, Solomon DA, Costello JF. Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas. Neuro Oncol. 2018 Apr 9;20(5):632-641. doi: 10.1093/neuonc/nox205. PubMed PMID: 29077933; PubMed Central PMCID: PMC5892142.

Stieglitz E, Mazor T, Olshen AB, Geng H, Gelston LC, Akutagawa J, Lipka DB, Plass C, Flotho C, Chehab FF, Braun BS, Costello JF, Loh ML. Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia. Nat Commun. 2017 Dec 19;8(1):2127. doi: 10.1038/s41467-017-02178-9. PubMed PMID: 29259179; PubMed Central PMCID: PMC5736624.

Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, Davidson S, Edwards M, Elvin JA, Hodel KP, Zahurancik WJ, Suo Z, Lipman T, Wimmer K, Kratz CP, Bowers DC, Laetsch TW, Dunn GP, Johanns TM, Grimmer MR, Smirnov IV, Larouche V, Samuel D, Bronsema A, Osborn M, Stearns D, Raman P, Cole KA, Storm PB, Yalon M, Opocher E, Mason G, Thomas GA, Sabel M, George B, Ziegler DS, Lindhorst S, Issai VM, Constantini S, Toledano H, Elhasid R, Farah R, Dvir R, Dirks P, Huang A, Galati MA, Chung J, Ramaswamy V, Irwin MS, Aronson M, Durno C, Taylor MD, Rechavi G, Maris JM, Bouffet E, Hawkins C, Costello JF, Meyn MS, Pursell ZF, Malkin D, Tabori U, Shlien A. Comprehensive Analysis of Hypermutation in Human Cancer. Cell. 2017 Nov 16;171(5):1042-1056.e10. doi: 10.1016/j.cell.2017.09.048. Epub 2017 Oct 19. PubMed PMID: 29056344; PubMed Central PMCID: PMC5849393.

Mazor T, Chesnelong C, Pankov A, Jalbert LE, Hong C, Hayes J, Smirnov IV, Marshall R, Souza CF, Shen Y, Viswanath P, Noushmehr H, Ronen SM, Jones SJM, Marra MA, Cairncross JG, Perry A, Nelson SJ, Chang SM, Bollen AW, Molinaro AM, Bengtsson H, Olshen AB, Weiss S, Phillips JJ, Luchman HA, Costello JF. Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1. Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10743-10748. doi: 10.1073/pnas.1708914114. Epub 2017 Sep 15. PubMed PMID: 28916733; PubMed Central PMCID: PMC5635900.

Wahl M, Chang SM, Phillips JJ, Molinaro AM, Costello JF, Mazor T, Alexandrescu S, Lupo JM, Nelson SJ, Berger M, Prados M, Taylor JW, Butowski N, Clarke JL, Haas-Kogan D. Probing the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in gliomas: A phase 2 study of everolimus for recurrent adult low-grade gliomas. Cancer. 2017 Dec 1;123(23):4631-4639. doi: 10.1002/cncr.30909. Epub 2017 Jul 31. PubMed PMID: 28759109; PubMed Central PMCID: PMC5693663.

Kohanbash G, Carrera DA, Shrivastav S, Ahn BJ, Jahan N, Mazor T, Chheda ZS, Downey KM, Watchmaker PB, Beppler C, Warta R, Amankulor NA, Herold-Mende C, Costello JF, Okada H. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. J Clin Invest. 2017 Apr 3;127(4):1425-1437. doi: 10.1172/JCI90644. Epub 2017 Mar 20. PubMed PMID: 28319047; PubMed Central PMCID: PMC5373859.

Venkatesan S, Swanton C, Taylor BS, Costello JF. Treatment-Induced Mutagenesis and Selective Pressures Sculpt Cancer Evolution. Cold Spring Harb Perspect Med. 2017 Mar 13. pii: a026617. doi: 10.1101/cshperspect.a026617. [Epub ahead of print] PubMed PMID: 28289245.

Ohba S, Mukherjee J, Johannessen TC, Mancini A, Chow TT, Wood M, Jones L, Mazor T, Marshall RE, Viswanath P, Walsh KM, Perry A, Bell RJ, Phillips JJ, Costello JF, Ronen SM, Pieper RO. Mutant IDH1 Expression Drives TERT Promoter Reactivation as Part of the Cellular Transformation Process. Cancer Res. 2016 Nov 15;76(22):6680-6689. doi: 10.1158/0008-5472.CAN-16-0696. Epub 2016 Oct 6. PubMed PMID: 27758882; PubMed Central PMCID: PMC5290072.

Sherborne AL, Lavergne V, Yu K, Lee L, Davidson PR, Mazor T, Smirnoff IV, Horvai AE, Loh M, DuBois SG, Goldsby RE, Neglia JP, Hammond S, Robison LL, Wustrack R, Costello JF, Nakamura AO, Shannon KM, Bhatia S, Nakamura JL. Somatic and Germline TP53 Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors. Clin Cancer Res. 2017 Apr 1;23(7):1852-1861. doi: 10.1158/1078-0432.CCR-16-0610. Epub 2016 Sep 28. PubMed PMID: 27683180.

Wahl M, Phillips JJ, Molinaro AM, Lin Y, Perry A, Haas-Kogan DA, Costello JF, Dayal M, Butowski N, Clarke JL, Prados M, Nelson S, Berger MS, Chang SM. Chemotherapy for adult low-grade gliomas: clinical outcomes by molecular subtype in a phase II study of adjuvant temozolomide. Neuro Oncol. 2017 Feb 1;19(2):242-251. doi: 10.1093/neuonc/now176. PubMed PMID: 27571885; PubMed Central PMCID: PMC5464133.

Viswanath P, Najac C, Izquierdo-Garcia JL, Pankov A, Hong C, Eriksson P, Costello JF, Pieper RO, Ronen SM. Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters. Oncotarget. 2016 Jun 7;7(23):34942-55. doi: 10.18632/oncotarget.9006. PubMed PMID: 27144334; PubMed Central PMCID: PMC5085201.

Mazor T, Pankov A, Song JS, Costello JF. Intratumoral Heterogeneity of the Epigenome. Cancer Cell. 2016 Apr 11;29(4):440-51. doi: 10.1016/j.ccell.2016.03.009. Review. PubMed PMID: 27070699; PubMed Central PMCID: PMC4852161.

Bell RJ, Rube HT, Xavier-Magalhães A, Costa BM, Mancini A, Song JS, Costello JF. Understanding TERT Promoter Mutations: A Common Path to Immortality. Mol Cancer Res. 2016 Apr;14(4):315-23. doi: 10.1158/1541-7786.MCR-16-0003. Epub 2016 Mar 3. Review. PubMed PMID: 26941407; PubMed Central PMCID: PMC4852159.

Gu J, Stevens M, Xing X, Li D, Zhang B, Payton JE, Oltz EM, Jarvis JN, Jiang K, Cicero T, Costello JF, Wang T. Mapping of Variable DNA Methylation Across Multiple Cell Types Defines a Dynamic Regulatory Landscape of the Human Genome. G3 (Bethesda). 2016 Apr 7;6(4):973-86. doi: 10.1534/g3.115.025437. PubMed PMID: 26888867; PubMed Central PMCID: PMC4825665.

Grimmer MR, Costello JF. Cancer: Oncogene brought into the loop. Nature. 2016 Jan 7;529(7584):34-5. doi: 10.1038/nature16330. Epub 2015 Dec 23. PubMed PMID: 26700812; PubMed Central PMCID: PMC4920076.

Stieglitz E, Taylor-Weiner AN, Chang TY, Gelston LC, Wang YD, Mazor T, Esquivel E, Yu A, Seepo S, Olsen SR, Rosenberg M, Archambeault SL, Abusin G, Beckman K, Brown PA, Briones M, Carcamo B, Cooper T, Dahl GV, Emanuel PD, Fluchel MN, Goyal RK, Hayashi RJ, Hitzler J, Hugge C, Liu YL, Messinger YH, Mahoney DH Jr, Monteleone P, Nemecek ER, Roehrs PA, Schore RJ, Stine KC, Takemoto CM, Toretsky JA, Costello JF, Olshen AB, Stewart C, Li Y, Ma J, Gerbing RB, Alonzo TA, Getz G, Gruber TA, Golub TR, Stegmaier K, Loh ML. The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet. 2015 Nov;47(11):1326-33. doi: 10.1038/ng.3400. Epub 2015 Oct 12. Erratum in: Nat Genet. 2015 Nov;47(11):1333. Nat Genet. 2016 Jan;48(1):101. PubMed PMID: 26457647; PubMed Central PMCID: PMC4626387.

Mazor T, Pankov A, Johnson BE, Hong C, Hamilton EG, Bell RJ, Smirnov IV, Reis GF, Phillips JJ, Barnes MJ, Idbaih A, Alentorn A, Kloezeman JJ, Lamfers ML, Bollen AW, Taylor BS, Molinaro AM, Olshen AB, Chang SM, Song JS, Costello JF. DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors. Cancer Cell. 2015 Sep 14;28(3):307-17. doi: 10.1016/j.ccell.2015.07.012. PubMed PMID: 26373278; PubMed Central PMCID: PMC4573399.

Bell RJ, Rube HT, Kreig A, Mancini A, Fouse SD, Nagarajan RP, Choi S, Hong C, He D, Pekmezci M, Wiencke JK, Wrensch MR, Chang SM, Walsh KM, Myong S, Song JS, Costello JF. Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science. 2015 May 29;348(6238):1036-9. doi: 10.1126/science.aab0015. Epub 2015 May 14. PubMed PMID: 25977370; PubMed Central PMCID: PMC4456397.

van Thuijl HF, Mazor T, Johnson BE, Fouse SD, Aihara K, Hong C, Malmström A, Hallbeck M, Heimans JJ, Kloezeman JJ, Stenmark-Askmalm M, Lamfers ML, Saito N, Aburatani H, Mukasa A, Berger MS, Söderkvist P, Taylor BS, Molinaro AM, Wesseling P, Reijneveld JC, Chang SM, Ylstra B, Costello JF. Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. Acta Neuropathol. 2015 Apr;129(4):597-607. doi: 10.1007/s00401-015-1403-6. Epub 2015 Feb 28. PubMed PMID: 25724300; PubMed Central PMCID: PMC4482618.

Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015 Feb 19;518(7539):317-30. doi: 10.1038/nature14248. PubMed PMID: 25693563; PubMed Central PMCID: PMC4530010.

Elliott G, Hong C, Xing X, Zhou X, Li D, Coarfa C, Bell RJ, Maire CL, Ligon KL, Sigaroudinia M, Gascard P, Tlsty TD, Harris RA, Schalkwyk LC, Bilenky M, Mill J, Farnham PJ, Kellis M, Marra MA, Milosavljevic A, Hirst M, Stormo GD, Wang T, Costello JF. Intermediate DNA methylation is a conserved signature of genome regulation. Nat Commun. 2015 Feb 18;6:6363. doi: 10.1038/ncomms7363. PubMed PMID: 25691127; PubMed Central PMCID: PMC4333717.

Zhou X, Li D, Zhang B, Lowdon RF, Rockweiler NB, Sears RL, Madden PA, Smirnov I, Costello JF, Wang T. Epigenomic annotation of genetic variants using the Roadmap Epigenome Browser. Nat Biotechnol. 2015 Apr;33(4):345-6. PubMed PMID: 25690851; PubMed Central PMCID: PMC4467764.

Ameri K, Jahangiri A, Rajah AM, Tormos KV, Nagarajan R, Pekmezci M, Nguyen V, Wheeler ML, Murphy MP, Sanders TA, Jeffrey SS, Yeghiazarians Y, Rinaudo PF, Costello JF, Aghi MK, Maltepe E. HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth. Cell Rep. 2015 Feb 12. pii: S2211-1247(15)00033-9. doi: 10.1016/j.celrep.2015.01.020. [Epub ahead of print] PubMed PMID: 25683712; PubMed Central PMCID: PMC4534363.

Chen J, Hackett CS, Zhang S, Song YK, Bell RJ, Molinaro AM, Quigley DA, Balmain A, Song JS, Costello JF, Gustafson WC, Van Dyke T, Kwok PY, Khan J, Weiss WA. The genetics of splicing in neuroblastoma. Cancer Discov. 2015 Apr;5(4):380-95. doi: 10.1158/2159-8290.CD-14-0892. Epub 2015 Jan 30. PubMed PMID: 25637275; PubMed Central PMCID: PMC4390477.

Zheng CL, Wang NJ, Chung J, Moslehi H, Sanborn JZ, Hur JS, Collisson EA, Vemula SS, Naujokas A, Chiotti KE, Cheng JB, Fassihi H, Blumberg AJ, Bailey CV, Fudem GM, Mihm FG, Cunningham BB, Neuhaus IM, Liao W, Oh DH, Cleaver JE, LeBoit PE, Costello JF, Lehmann AR, Gray JW, Spellman PT, Arron ST, Huh N, Purdom E, Cho RJ. Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes. Cell Rep. 2014 Nov 20;9(4):1228-34. doi: 10.1016/j.celrep.2014.10.031. Epub 2014 Nov 20. PubMed PMID: 25456125; PubMed Central PMCID: PMC4254608.

Lowdon RF, Zhang B, Bilenky M, Mauro T, Li D, Gascard P, Sigaroudinia M, Farnham PJ, Bastian BC, Tlsty TD, Marra MA, Hirst M, Costello JF, Wang T, Cheng JB. Regulatory network decoded from epigenomes of surface ectoderm-derived cell types. Nat Commun. 2014 Nov 25;5:5442. doi: 10.1038/ncomms6442. PubMed PMID: 25421844; PubMed Central PMCID: PMC4385735.

Zhou X, Li D, Lowdon RF, Costello JF, Wang T. methylC Track: visual integration of single-base resolution DNA methylation data on the WashU EpiGenome Browser. Bioinformatics. 2014 Aug 1;30(15):2206-7. doi: 10.1093/bioinformatics/btu191. Epub 2014 Apr 10. PubMed PMID: 24728854; PubMed Central PMCID: PMC4103599.

Younesy H, Möller T, Heravi-Moussavi A, Cheng JB, Costello JF, Lorincz MC, Karimi MM, Jones SJ. ALEA: a toolbox for allele-specific epigenomics analysis. Bioinformatics. 2014 Apr 15;30(8):1172-1174. Epub 2013 Dec 26. PubMed PMID: 24371156.

Nagarajan RP, Zhang B, Bell RJ, Johnson BE, Olshen AB, Sundaram V, Li D, Graham AE, Diaz A, Fouse SD, Smirnov I, Song J, Paris PL, Wang T, Costello JF. Recurrent epimutations activate gene body promoters in primary glioblastoma. Genome Res. 2014 May;24(5):761-74. doi: 10.1101/gr.164707.113. Epub 2014 Apr 7. PubMed PMID: 24709822; PubMed Central PMCID: PMC4009606.

Clarke JL, Molinaro AM, Phillips JJ, Butowski NA, Chang SM, Perry A, Costello JF, DeSilva AA, Rabbitt JE, Prados MD. A single-institution phase II trial of radiation, temozolomide, erlotinib, and bevacizumab for initial treatment of glioblastoma. Neuro Oncol. 2014 Jul;16(7):984-90. PubMed PMID: 24637230; PubMed Central PMCID: PMC4057142.

Sturm D, Bender S, Jones DT, Lichter P, Grill J, Becher O, Hawkins C, Majewski J, Jones C, Costello JF, Iavarone A, Aldape K, Brennan CW, Jabado N, Pfister SM. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer. 2014 Feb;14(2):92-107. doi: 10.1038/nrc3655. Review. PubMed PMID: 24457416; PubMed Central PMCID: PMC4003223.

Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, Fouse SD, Yamamoto S, Ueda H, Tatsuno K, Asthana S, Jalbert LE, Nelson SJ, Bollen AW, Gustafson WC, Charron E, Weiss WA, Smirnov IV, Song JS, Olshen AB, Cha S, Zhao Y, Moore RA, Mungall AJ, Jones SJ, Hirst M, Marra MA, Saito N, Aburatani H, Mukasa A, Berger MS, Chang SM, Taylor BS, Costello JF. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014 Jan 10;343(6167):189-93. doi: 10.1126/science.1239947. Epub 2013 Dec 12. PubMed PMID: 24336570; PubMed Central PMCID: PMC3998672.

Fouse SD, Nakamura JL, James CD, Chang S, Costello JF. Response of primary glioblastoma cells to therapy is patient specific and independent of cancer stem cell phenotype. Neuro Oncol. 2014 Mar;16(3):361-71. doi: 10.1093/neuonc/not223. Epub 2013 Dec 4. PubMed PMID: 24311636; PubMed Central PMCID: PMC3922516.

Huse JT, Wallace M, Aldape KD, Berger MS, Bettegowda C, Brat DJ, Cahill DP, Cloughesy T, Haas-Kogan DA, Marra M, Miller CR, Nelson SJ, Salama SR, Soffietti R, Wen PY, Yip S, Yen K, Costello JF, Chang S. Where are we now? And where are we going? A report from the Accelerate Brain Cancer Cure (ABC2) low-grade glioma research workshop. Neuro Oncol. 2014 Jan;16(2):173-8. doi: 10.1093/neuonc/not229. Epub 2013 Dec 4. Review. PubMed PMID: 24305708; PubMed Central PMCID: PMC3895389.