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Joe Costello, PhD

Joe Costello, PhD
Professor, Neurological Surgery
Karen Osney Brownstein Endowed Chair
Research Summary:
Mechanistic and Translational Cancer Research using Genomic and Epigenomic Approaches

The Costello laboratory is composed of molecular and computational biologists working alongside clinician-scientists.  Our goal is to understand the full life history of human 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 alternations and gene expression changes. 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.  In collaboration with the Okada laboratory, we will be exploring the application of immune therapies to target tumor specific mutations and tumors that emerge as hypermutated following chemotherapy.  On the gene level, we recently discovered the mechanism by which mutation in the TERT gene promoter leads to telomerase activation, and are pursuing further mechanistic and therapeutic studies aimed at reversing tumor cell immortalization. TERT promoter mutation is one of the most common mutations in cancer in adults.

Selected Publications

Bell RJ, Rube HT, Kreig A, Mancini A, Fouse SF, Nagarajan RP, Choi S, Hong C, He D, Pekmezci M, Wiencke JK, Wrensch MR, Chang SM, Walsh KM, Myong S, Song JS, Costello JF. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science. 2015 May 29;348(6238):1036-9. 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. PMC4482618.

The NIH Roadmap Epigenome Consortium. Integrative analysis of 111 reference human epigenomes. Nature, Feb 18, 2015, 19;518(7539):317-30.

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. PMC3998672.

Xie M, Hong C, Zhang B, Lowdon RF, Xing X, Li D, Zhou X, Lee HJ, Maire CL, Ligon KL, Gascard P, Sigaroudinia M, Tlsty TD, Kadlecek T, Weiss A, O'Geen H, Farnham PJ, Madden PA, Mungall AJ, Tam A, Kamoh B, Cho S, Moore R, Hirst M, Marra MA, *Costello JF, *Wang T. DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape. Nat Genet. 2013 May 26. doi: 10.1038/ng.2649. *co-corresponding authors

Zhou X, Lowdon RF, Li D, Lawson HA, Madden PA, *Costello JF, *Wang T. Exploring long-range genome interactions using the WashU Epigenome Browser. Nat Methods. 2013 May;10(5):375-5. doi: 10.1038/nmeth.2440. *co-corresponding authors

Maunakea AK, Nagarajan, RP, Bilenky M, Ballinger TJ, D'Souza C, Fouse SD, Johnson BE, Hong C, Nielson C, Zhao Y, Turecki G, Delaney A, Varhol R, Thiessen N, Shchors K, Heine VM, Rowitch DH, Xing X, Fiore C, Schillebeeckx M, Jones SSJ, Haussler D, Marra MA, Hirst M, Wang T, Costello JF. Evolutionarily Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters. Nature, 2010 Jul 8;466(7303):253-7.

Harris RA, Wang T, Coarfa C, Zhou X, Xi Y, Nagarajan RP, Hong C, Downey S, Johnson BE, Fouse SD, Delaney A, Zhao Y, Olshen A, Ballinger T, Zhou X, Forsberg KJ, Gu J, Echipare L, O'Geen H Lister R, Pelizzola M, Xi Y, Epstein CB, Bernstein BE, Hawkins RD, Ren B, Chung WY, Gu H, Bock C, Gnirke A, Zhang MQ, Haussler D, Ecker J, Li W, Farnham PJ, Waterland RA, Meissner A, Marra MA, Hirst M, Milosavljevic A, Costello JF. Sequence-based profiling of DNA methylation: comparisons of methods and catalogue of allelic epigenetic modifications. Nature Biotechnology 2010 Oct;28(10):1097-105. Epub 2010 Sep 19.

Costello JF. Stem Cells: Tips for priming potency (editorial). Nature 2008 July 3, 454, 45-46.