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Status |
Public on May 13, 2024 |
Title |
Scalable, compressed phenotypic screening using pooled perturbations (PDAC screens) |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
High-throughput phenotypic screens leveraging biochemical perturbations and high-content readouts are poised to advance therapeutic discovery, yet they remain constrained by limitations of scale. To address this, we establish a method of pooling exogenous perturbations followed by computational deconvolution to compress a screen’s required sample, labor, and financial input. We benchmark the approach with a bioactive small molecule library and a high-content imaging readout, demonstrating the feasibility and increased efficiency of compressed experimental designs compared to conventional approaches. To prove generalizability, we apply compressed screening in two different biological discovery campaigns. In the first, we use early-passage pancreatic cancer organoids to map transcriptional responses to alibrary oftumor-microenvironmentrecombinant protein ligands. We uncover reproducible phenotypic shifts induced by specific ligands that are distinct from canonical reference signatures and uniquely correlate with clinical outcome.In the second, we examine the modulatory effects of a known mechanism of action chemical compound library on primary human peripheral blood mononuclear cell immune responses. Through contrastive analyses, we identify molecules that potentiate and/or inhibit cell-type specific transcriptional features, uncover pleiotropic effects for individual compounds across diverse cell types, and realize a systems-level view of drug responses. In sum, our approach empowers phenotypic screens with information-rich readouts to advance drug discovery efforts as well as basic biological inquiry.
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Overall design |
Patient-derived pancreatic cancer (PDAC) organoids from patients with metastatic pancreatic cancer (Raghavan et al., Cell, 2021) were screened with a library of 68 macrophage-derived ligands (and DMSO control) for the compressed screen and 11 ligands (and DMSO control) for the validation experiment for 7 days and analyzed using scRNA-seq.
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Web link |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9900857/
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Contributor(s) |
Liu N, Kattan WE, Mead BE, Kummerlowe C, Cheng T, Ingabire S, Cheah JH, Soule CK, Vrcic A, McIninch JK, Triana S, Guzman M, Dao TT, Peters JM, Lowder KE, Crawford L, Amini AP, Blainey PC, Hahn WC, Cleary B, Bryson B, Winter PS, Raghavan S, Shalek AK |
Citation(s) |
36747859 |
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Submission date |
May 12, 2024 |
Last update date |
Aug 12, 2024 |
Contact name |
Alex K. Shalek |
Organization name |
MIT
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Street address |
77 Massachusetts Ave
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City |
Cambridge |
State/province |
MA |
ZIP/Postal code |
02139 |
Country |
USA |
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Platforms (1) |
GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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Samples (54)
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GSM8262832 |
PDAC compressed screen, plate 1 column 1, hash |
GSM8262833 |
PDAC compressed screen, plate 1 column 2, hash |
GSM8262834 |
PDAC compressed screen, plate 1 column 3, hash |
GSM8262835 |
PDAC compressed screen, plate 1 column 4, hash |
GSM8262836 |
PDAC compressed screen, plate 1 column 5, hash |
GSM8262837 |
PDAC compressed screen, plate 1 column 6, hash |
GSM8262838 |
PDAC compressed screen, plate 1 column 7,hash |
GSM8262839 |
PDAC compressed screen, plate 1 column 8, hash |
GSM8262840 |
PDAC compressed screen, plate 2 column 1, hash |
GSM8262841 |
PDAC compressed screen, plate 2 column 2, hash |
GSM8262842 |
PDAC compressed screen, plate 2 column 3, hash |
GSM8262843 |
PDAC compressed screen, plate 2 column 4, hash |
GSM8262844 |
PDAC compressed screen, plate 2 column 5,hash |
GSM8262845 |
PDAC compressed screen, plate 2 column 6, hash |
GSM8262846 |
PDAC compressed screen, plate 2 column 7, hash |
GSM8262847 |
PDAC compressed screen, plate 2 column 8, hash |
GSM8262848 |
PDAC compressed screen, plate 1 column 1, cDNA |
GSM8262849 |
PDAC compressed screen, plate 1 column 2, cDNA |
GSM8262850 |
PDAC compressed screen, plate 1 column 3, cDNA |
GSM8262851 |
PDAC compressed screen, plate 1 column 4, cDNA |
GSM8262852 |
PDAC compressed screen, plate 1 column 5, cDNA |
GSM8262853 |
PDAC compressed screen, plate 1 column 6, cDNA |
GSM8262854 |
PDAC compressed screen, plate 1 column 7, cDNA |
GSM8262855 |
PDAC compressed screen, plate 1 column 8, cDNA |
GSM8262856 |
PDAC compressed screen, plate 2 column 1, cDNA |
GSM8262857 |
PDAC compressed screen, plate 2 column 2, cDNA |
GSM8262858 |
PDAC compressed screen, plate 2 column 3, cDNA |
GSM8262859 |
PDAC compressed screen, plate 2 column 4, cDNA |
GSM8262860 |
PDAC compressed screen, plate 2 column 5, cDNA |
GSM8262861 |
PDAC compressed screen, plate 2 column 6, cDNA |
GSM8262862 |
PDAC compressed screen, plate 2 column 7, cDNA |
GSM8262863 |
PDAC compressed screen, plate 2 column 8, cDNA |
GSM8262864 |
PDAC validation experiment 1, D7, row 1, hash |
GSM8262865 |
PDAC validation experiment 1, D7, row 2, hash |
GSM8262866 |
PDAC validation experiment 1, D7, row3, hash |
GSM8262867 |
PDAC validation experiment 1, D7, row 4, hash |
GSM8262868 |
PDAC validation experiment 1, D7, row 5, hash |
GSM8262869 |
PDAC validation experiment 1, D7, row 6, hash |
GSM8262870 |
PDAC validation experiment 1, D7, row 1, cDNA |
GSM8262871 |
PDAC validation experiment 1, D7, row 2,cDNA |
GSM8262872 |
PDAC validation experiment 1, D7, row3, cDNA |
GSM8262873 |
PDAC validation experiment 1, D7, row 4, cDNA |
GSM8262874 |
PDAC validation experiment 1, D7, row 5,cDNA |
GSM8262875 |
PDAC validation experiment 1, D7, row 6,cDNA |
GSM8262876 |
PDAC validation experiment 2, D7, row 1,hash |
GSM8262877 |
PDAC validation experiment 2, D7, row 2,hash |
GSM8262878 |
PDAC validation experiment 2, D7, row 3,hash |
GSM8262879 |
PDAC validation experiment 2, D7, row 4,hash |
GSM8262880 |
PDAC validation experiment 2, D7, row 5,hash |
GSM8262881 |
PDAC validation experiment 2, D7, row 1,cDNA |
GSM8262882 |
PDAC validation experiment 2, D7, row 2,cDNA |
GSM8262883 |
PDAC validation experiment 2, D7, row 3,cDNA |
GSM8262884 |
PDAC validation experiment 2, D7, row 4,cDNA |
GSM8262885 |
PDAC validation experiment 2, D7, row 5,cDNA |
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Relations |
BioProject |
PRJNA1110737 |
Supplementary file |
Size |
Download |
File type/resource |
GSE267243_RAW.tar |
235.1 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
Raw data are available in SRA |
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