TY  - JOUR
AU  - Mircetic, Jovan
AU  - Camgöz, Aylin
AU  - Abohawya, Moustafa
AU  - Ding, Li
AU  - Dietzel, Julia
AU  - Tobar, Sebastián García
AU  - Paszkowski-Rogacz, Maciej
AU  - Seidlitz, Therese
AU  - Schmäche, Tim
AU  - Mehnert, Marie-Christin
AU  - Sidorova, Olga
AU  - Weitz, Jürgen
AU  - Buchholz, Frank
AU  - Stange, Daniel E
TI  - CRISPR/Cas9 Screen in Gastric Cancer Patient-Derived Organoids Reveals KDM1A-NDRG1 Axis as a Targetable Vulnerability.
JO  - Small Methods
VL  - 7
IS  - 6
SN  - 2366-9608
CY  - Weinheim
PB  - WILEY-VCH Verlag GmbH & Co. KGaA
M1  - DKFZ-2023-00516
SP  - e2201605
PY  - 2023
N1  - 2023 Jun;7(6):e2201605
AB  - 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
KW  - CRISPR screen (Other)
KW  - KDM1A-NDRG1 axis (Other)
KW  - epigenetic regulators (Other)
KW  - gastric cancer (Other)
KW  - patient-derived organoids (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36908010
DO  - DOI:10.1002/smtd.202201605
UR  - https://inrepo02.dkfz.de/record/274230
ER  -