Professional Education

  • Master of Science, University Of Ioannina (2012)
  • Diplom, University Of Ioannina (2009)
  • Doctor of Philosophy, Heidelberg College (2016)

Contact

  • Academic
    drainas@stanford.edu
    University - Scholar Department: Pediatrics Position: Postdoctoral Scholar

All Publications

  • Genome-wide Screens Implicate Loss of Cullin Ring Ligase 3 in Persistent Proliferation and Genome Instability in TP53-Deficient Cells CELL REPORTS Drainas, A. P., Lambuta, R. A., Ivanova, I., Sercin, O., Sarropoulos, I., Smith, M. L., Efthymiopoulos, T., Raeder, B., Stuetz, A. M., Waszak, S. M., Mardin, B. R., Korbel, J. O. 2020; 31 (1): 107465

    Abstract

    TP53 deficiency is the most common alteration in cancer; however, this alone is typically insufficient to drive tumorigenesis. To identify genes promoting tumorigenesis in combination with TP53 deficiency, we perform genome-wide CRISPR-Cas9 knockout screens coupled with proliferation and transformation assays in isogenic cell lines. Loss of several known tumor suppressors enhances cellular proliferation and transformation. Loss of neddylation pathway genes promotes uncontrolled proliferation exclusively in TP53-deficient cells. Combined loss of CUL3 and TP53 activates an oncogenic transcriptional program governed by the nuclear factor κB (NF-κB), AP-1, and transforming growth factor β (TGF-β) pathways. This program maintains persistent cellular proliferation, induces partial epithelial to mesenchymal transition, and increases DNA damage, genomic instability, and chromosomal rearrangements. Our findings reveal CUL3 loss as a key event stimulating persistent proliferation in TP53-deficient cells. These findings may be clinically relevant, since TP53-CUL3-deficient cells are highly sensitive to ataxia telangiectasia mutated (ATM) inhibition, exposing a vulnerability that could be exploited for cancer treatment.

    View details for DOI 10.1016/j.celrep.2020.03.029

    View details for Web of Science ID 000524976500009

    View details for PubMedID 32268084

    View details for PubMedCentralID PMC7166082

  • The MEK5-ERK5 kinase axis controls lipid metabolism in small cell lung cancer. Cancer research Cristea, S., Coles, G. L., Hornburg, D., Gershkovitz, M., Arand, J., Cao, S., Sen, T., Williamson, S. C., Kim, J. W., Drainas, A. P., He, A., Le Cam, L., Byers, L. A., Snyder, M. P., Contrepois, K., Sage, J. 2020

    Abstract

    Small cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here we investigated the contribution of the MAP kinase module MEK5/ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacological inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC.

    View details for DOI 10.1158/0008-5472.CAN-19-1027

    View details for PubMedID 31969375

  • Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells. Cancer cell Coles, G. L., Cristea, S., Webber, J. T., Levin, R. S., Moss, S. M., He, A., Sangodkar, J., Hwang, Y. C., Arand, J., Drainas, A. P., Mooney, N. A., Demeter, J., Spradlin, J. N., Mauch, B., Le, V., Shue, Y. T., Ko, J. H., Lee, M. C., Kong, C., Nomura, D. K., Ohlmeyer, M., Swaney, D. L., Krogan, N. J., Jackson, P. K., Narla, G., Gordan, J. D., Shokat, K. M., Sage, J. 2020

    Abstract

    Using unbiased kinase profiling, we identified protein kinase A (PKA) as an active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity genetically, or pharmacologically by activation of the PP2A phosphatase, suppresses SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein α subunit), a PKA activator that is genetically activated in a small subset of human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many PKA substrates and mechanisms of action. In particular, PKA activity is required for the propagation of SCLC stem cells in transplantation studies. Broad proteomic analysis of recalcitrant cancers has the potential to uncover targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.

    View details for DOI 10.1016/j.ccell.2020.05.003

    View details for PubMedID 32531271

  • Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability. The Journal of cell biology Achuthankutty, D., Thakur, R. S., Haahr, P., Hoffmann, S., Drainas, A. P., Bizard, A. H., Weischenfeldt, J., Hickson, I. D., Mailand, N. 2019

    Abstract

    The ATR kinase is a master regulator of the cellular response to DNA replication stress. Activation of ATR relies on dual pathways involving the TopBP1 and ETAA1 proteins, both of which harbor ATR-activating domains (AADs). However, the exact contribution of the recently discovered ETAA1 pathway to ATR signaling in different contexts remains poorly understood. Here, using an unbiased CRISPR-Cas9-based genome-scale screen, we show that the ATR-stimulating function of ETAA1 becomes indispensable for cell fitness and chromosome stability when the fidelity of DNA replication is compromised. We demonstrate that the ATR-activating potential of ETAA1 is controlled by cell cycle- and replication stress-dependent phosphorylation of highly conserved residues within its AAD, and that the stimulatory impact of these modifications is required for the ability of ETAA1 to prevent mitotic chromosome abnormalities following replicative stress. Our findings suggest an important role of ETAA1 in protecting against genome instability arising from incompletely duplicated DNA via regulatory control of its ATR-stimulating potential.

    View details for DOI 10.1083/jcb.201905064

    View details for PubMedID 31615875

  • Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nature genetics Weischenfeldt, J., Dubash, T., Drainas, A. P., Mardin, B. R., Chen, Y., Stütz, A. M., Waszak, S. M., Bosco, G., Halvorsen, A. R., Raeder, B., Efthymiopoulos, T., Erkek, S., Siegl, C., Brenner, H., Brustugun, O. T., Dieter, S. M., Northcott, P. A., Petersen, I., Pfister, S. M., Schneider, M., Solberg, S. K., Thunissen, E., Weichert, W., Zichner, T., Thomas, R., Peifer, M., Helland, A., Ball, C. R., Jechlinger, M., Sotillo, R., Glimm, H., Korbel, J. O. 2017; 49 (1): 65–74

    Abstract

    Extensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g., enhancer hijacking) by integrating SCNAs, gene expression data and information on topologically associating domains (TADs). Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer is associated with recurrent deletions in cis, and we present evidence supporting a tumor-promoting role. We additionally pursued cancer-type-specific analyses and uncovered IGF2 as a target for enhancer hijacking in colorectal cancer. Recurrent tandem duplications intersecting with a TAD boundary mediate de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, resulting in high-level gene activation. Our framework enables systematic inference of CRE rearrangements mediating dysregulation in cancer.

    View details for DOI 10.1038/ng.3722

    View details for PubMedID 27869826

    View details for PubMedCentralID PMC5791882

  • A cell-based model system links chromothripsis with hyperploidy. Molecular systems biology Mardin, B. R., Drainas, A. P., Waszak, S. M., Weischenfeldt, J., Isokane, M., Stütz, A. M., Raeder, B., Efthymiopoulos, T., Buccitelli, C., Segura-Wang, M., Northcott, P., Pfister, S. M., Lichter, P., Ellenberg, J., Korbel, J. O. 2015; 11 (9): 828

    Abstract

    A remarkable observation emerging from recent cancer genome analyses is the identification of chromothripsis as a one-off genomic catastrophe, resulting in massive somatic DNA structural rearrangements (SRs). Largely due to lack of suitable model systems, the mechanistic basis of chromothripsis has remained elusive. We developed an integrative method termed "complex alterations after selection and transformation (CAST)," enabling efficient in vitro generation of complex DNA rearrangements including chromothripsis, using cell perturbations coupled with a strong selection barrier followed by massively parallel sequencing. We employed this methodology to characterize catastrophic SR formation processes, their temporal sequence, and their impact on gene expression and cell division. Our in vitro system uncovered a propensity of chromothripsis to occur in cells with damaged telomeres, and in particular in hyperploid cells. Analysis of primary medulloblastoma cancer genomes verified the link between hyperploidy and chromothripsis in vivo. CAST provides the foundation for mechanistic dissection of complex DNA rearrangement processes.

    View details for DOI 10.15252/msb.20156505

    View details for PubMedID 26415501

    View details for PubMedCentralID PMC4592670