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Title: Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses
Patient-derived organoids (PDOs) can model personalized therapy responses; however, current screening technologies cannot reveal drug response mechanisms or how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly multiplexed mass cytometry platform to measure post- translational modification (PTM) signaling, DNA damage, cell-cycle activity, and apoptosis in >2,500 colorectal cancer (CRC) PDOs and cancer-associated fibroblasts (CAFs) in response to clinical therapies at single-cell resolution. To compare patient- and microenvironment-specific drug responses in thousands of single-cell da- tasets, we developed ‘‘Trellis’’—a highly scalable, tree-based treatment effect analysis method. Trellis single- cell screening revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. However, drug-induced apoptosis is rarer, patient-specific, and aligns with cancer cell PTM signaling. We find that CAFs can regulate PDO plasticity—shifting proliferative colonic stem cells (proCSCs) to slow-cycling revival colonic stem cells (revCSCs) to protect cancer cells from chemotherapy.  more » « less
Award ID(s):
2047856
PAR ID:
10546445
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ; ; ;
Publisher / Repository:
Cell Press
Date Published:
Journal Name:
Cell
Volume:
186
Issue:
25
ISSN:
0092-8674
Page Range / eLocation ID:
5606 to 5619.e24
Subject(s) / Keyword(s):
Single cell Optimal transport Patient-derived Organoids Phenoscape
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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