Compressed phenotypic screens for complex multicellular models and high-content assays.

Autor:	Mead BE; Institute for Medical Engineering and Science (IMES), Department of Chemistry, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Ragon Institute of MGH, MIT, and Harvard; Cambridge, MA, 02139, USA., Kummerlowe C; Institute for Medical Engineering and Science (IMES), Department of Chemistry, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Ragon Institute of MGH, MIT, and Harvard; Cambridge, MA, 02139, USA.; Program in Computational and Systems Biology, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA., Liu N; Institute for Medical Engineering and Science (IMES), Department of Chemistry, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Ragon Institute of MGH, MIT, and Harvard; Cambridge, MA, 02139, USA.; Program in Computational and Systems Biology, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA., Kattan WE; Institute for Medical Engineering and Science (IMES), Department of Chemistry, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Ragon Institute of MGH, MIT, and Harvard; Cambridge, MA, 02139, USA., Cheng T; Institute for Medical Engineering and Science (IMES), Department of Chemistry, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Ragon Institute of MGH, MIT, and Harvard; Cambridge, MA, 02139, USA., Cheah JH; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA., Soule CK; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA., Peters J; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Ragon Institute of MGH, MIT, and Harvard; Cambridge, MA, 02139, USA.; Harvard Medical School; Boston, MA, 02115, USA., Lowder KE; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Dana Farber Cancer Institute, Boston, MA, 02215, USA., Blainey PC; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Department of Biological Engineering, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA., Hahn WC; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Dana Farber Cancer Institute, Boston, MA, 02215, USA.; Harvard Medical School; Boston, MA, 02115, USA., Cleary B; Faculty of Computing and Data Sciences, Department of Biomedical Engineering, Department of Biology, Boston University; Boston, MA, 02215, USA., Bryson B; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Ragon Institute of MGH, MIT, and Harvard; Cambridge, MA, 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA., Winter PS; Institute for Medical Engineering and Science (IMES), Department of Chemistry, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Dana Farber Cancer Institute, Boston, MA, 02215, USA., Raghavan S; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Dana Farber Cancer Institute, Boston, MA, 02215, USA.; Harvard Medical School; Boston, MA, 02115, USA., Shalek AK; Institute for Medical Engineering and Science (IMES), Department of Chemistry, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Broad Institute of MIT and Harvard; Cambridge, MA, 02142, USA.; Ragon Institute of MGH, MIT, and Harvard; Cambridge, MA, 02139, USA.; Program in Computational and Systems Biology, Massachusetts Institute of Technology; Cambridge, MA, 02139, USA.; Program in Immunology, Harvard Medical School; Boston, MA, 02115, USA.; Harvard Stem Cell Institute; Cambridge, MA, 02138, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jan 23. Date of Electronic Publication: 2023 Jan 23.
DOI:	10.1101/2023.01.23.525189
Abstrakt:	High-throughput phenotypic screens leveraging biochemical perturbations, high-content readouts, and complex multicellular models could advance therapeutic discovery yet remain constrained by limitations of scale. To address this, we establish a method for compressing screens by pooling perturbations followed by computational deconvolution. Conducting controlled benchmarks with a highly bioactive small molecule library and a high-content imaging readout, we demonstrate increased efficiency for compressed experimental designs compared to conventional approaches. To prove generalizability, we apply compressed screening to examine transcriptional responses of patient-derived pancreatic cancer organoids to a library of tumor-microenvironment (TME)-nominated recombinant protein ligands. Using single-cell RNA-seq as a readout, we uncover reproducible phenotypic shifts induced by ligands that correlate with clinical features in larger datasets and are distinct from reference signatures available in public databases. In sum, our approach enables phenotypic screens that interrogate complex multicellular models with rich phenotypic readouts to advance translatable drug discovery as well as basic biology. Competing Interests: Declaration of Interests A.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Hovione, Third Rock Ventures, Ochre Bio, FL82, Empress Therapeutics, Relation Therapeutics, Senda Biosciences, IntrECate biotherapeutics, Santa Ana Bio and Dahlia Biosciences unrelated to this work. B.E.M. reports compensation for consulting from Empress Therapeutics unrelated to this work. S.R. holds equity in Amgen. P.C.B. is a consultant to or holds equity in 10X Genomics, General Automation Lab Technologies/Isolation Bio, Celsius Therapeutics, Next Gen Diagnostics, Cache DNA, Concerto Biosciences, Stately, Ramona Optics, and Bifrost. W.C.H. is a consultant for Thermo Fisher, Solasta Ventures, MPM Capital, KSQ Therapeutics, Tyra Biosciences, Jubilant Therapeutics, RAPPTA Therapeutics, Function Oncology, Riva Therapeutics, Serinus Biosciences, Frontier Medicines and Calyx.
Databáze:	MEDLINE
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