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@ARTICLE{Mircetic:274230,
      author       = {J. Mircetic$^*$ and A. Camgöz$^*$ and M. Abohawya$^*$ and
                      L. Ding and J. Dietzel and S. G. Tobar and M.
                      Paszkowski-Rogacz and T. Seidlitz and T. Schmäche and M.-C.
                      Mehnert and O. Sidorova and J. Weitz and F. Buchholz and D.
                      E. Stange$^*$},
      title        = {{CRISPR}/{C}as9 {S}creen in {G}astric {C}ancer
                      {P}atient-{D}erived {O}rganoids {R}eveals {KDM}1{A}-{NDRG}1
                      {A}xis as a {T}argetable {V}ulnerability.},
      journal      = {Small Methods},
      volume       = {7},
      number       = {6},
      issn         = {2366-9608},
      address      = {Weinheim},
      publisher    = {WILEY-VCH Verlag GmbH $\&$ Co. KGaA},
      reportid     = {DKFZ-2023-00516},
      pages        = {e2201605},
      year         = {2023},
      note         = {2023 Jun;7(6):e2201605},
      abstract     = {Viability CRISPR screens have proven indispensable in
                      parsing genome function. However, their application in new,
                      more physiologically relevant culturing systems like
                      patient-derived organoids (PDOs) has been much slower. To
                      probe epigenetic contribution to gastric cancer (GC), the
                      third leading cause of cancer-related deaths worldwide, the
                      first negative selection CRISPR screen in GC PDOs that
                      faithfully preserve primary tumor characteristics is
                      performed. Extensive quality control measurements showing
                      feasibility of CRISPR screens in primary organoid culture
                      are provided. The screen reveals the histone lysine
                      demethylase-1A (KDM1A) to constitute a GC vulnerability.
                      Both genetic and pharmacological inhibition of KDM1A cause
                      organoid growth retardation. Further, it is shown that most
                      of KDM1A cancer-supporting functions center on repression of
                      N-myc downstream regulates gene-1 (NDRG1). De-repression of
                      NDRG1 by KDM1A inhibitors (KDM1Ai) causes inhibition of Wnt
                      signaling and a strong G1 cell cycle arrest. Finally, by
                      profiling 20 GC PDOs, it is shown that NDRG1 upregulation
                      predicts KDM1Ai response with $100\%$ sensitivity and $82\%$
                      specificity in the tested cohort. Thus, this work pioneers
                      the use of negative selection CRISPR screens in
                      patient-derived organoids, identifies a marker of KDM1Ai
                      response, and accordingly a cohort of patients who may
                      benefit from such therapy.},
      keywords     = {CRISPR screen (Other) / KDM1A-NDRG1 axis (Other) /
                      epigenetic regulators (Other) / gastric cancer (Other) /
                      patient-derived organoids (Other)},
      cin          = {DD01 / B062 / HD01},
      ddc          = {620},
      cid          = {I:(DE-He78)DD01-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36908010},
      doi          = {10.1002/smtd.202201605},
      url          = {https://inrepo02.dkfz.de/record/274230},
}