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Single-cell screening of heterocellular patient-derived organoid drug responses

Ramos Zapatero, María; (2023) Single-cell screening of heterocellular patient-derived organoid drug responses. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Patient-derived organoids (PDOs) can model personalised therapy responses. However, current PDO screening technologies cannot reveal drug response mechanisms or study how cells of the tumour microenvironment alter therapeutic performance. To address this, I optimised the TOBis MC platform established in our lab to develop a highly-multiplexed mass cytometry screening platform to measure post-translational modification (PTM) signalling in >2,500 colorectal cancer (CRC) PDOs and cancer-associated fibroblasts (CAFs) in response to clinical therapies at a single-cell resolution. To compare patient- and microenvironment-specific drug responses across thousands of single-cell datasets, a highly-scalable analysis method was developed – Trellis. Trellis enables fast and accurate hierarchical tree-based treatment effect analysis across thousands of distributions. 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 patient-specific. Drug-induced apoptosis does not correlate with genotype or clinical staging but does align with cell-intrinsic PTM signalling in PDOs. CAFs protect chemosensitive PDOs by shifting cancer cells into a slow-cycling cell-state and CAF chemoprotection can be reversed by inhibiting YAP.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Single-cell screening of heterocellular patient-derived organoid drug responses
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10166749
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