An in vivo multiplexed small-molecule screening platform.
Phenotype-based small-molecule screening is a powerful method to identify molecules that regulate cellular functions. However, such screens are generally performed in vitro under conditions that do not necessarily model complex physiological conditions or disease states. Here, we use molecular cell barcoding to enable direct in vivo phenotypic screening of small-molecule libraries. The multiplexed nature of this approach allows rapid in vivo analysis of hundreds to thousands of compounds. Using this platform, we screened >700 covalent inhibitors directed toward hydrolases for their effect on pancreatic cancer metastatic seeding. We identified multiple hits and confirmed the relevant target of one compound as the lipase ABHD6. Pharmacological and genetic studies confirmed the role of this enzyme as a regulator of metastatic fitness. Our results highlight the applicability of this multiplexed screening platform for investigating complex processes in vivo.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Barbara M
BM
Grüner
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Christopher J
CJ
Schulze
Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
Dian
D
Yang
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
Daisuke
D
Ogasawara
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
Melissa M
MM
Dix
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Zoë N
ZN
Rogers
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Chen-Hua
CH
Chuang
Department of Biology, Stanford University, Stanford, CA, USA.
Christopher D
CD
McFarland
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Shin-Heng
SH
Chiou
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
J Mark
JM
Brown
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
Benjamin F
BF
Cravatt
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.|Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Matthew
M
Bogyo
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.|Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.|Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Monte M
MM
Winslow
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D055785:Gene Knockdown Techniques; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D057054:Molecular Imaging / Q000379:methods*; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000235:genetics; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D054852:Small Molecule Libraries / Q000494:pharmacology*
D054852:Small Molecule Libraries; C540878:ABHD6 protein, human; C527261:ABHD6 protein, mouse; D008994:Monoacylglycerol Lipases