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| Status |
Public on May 22, 2024 |
| Title |
Cellular adaptation to cancer therapy along a resistance continuum [CRISPR-Screen: Kuramochi] |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
Advancements in precision oncology over the past decades have led to new therapeutic interventions, but the efficacy of such treatments is generally limited by an adaptive process that fosters drug resistance. Beyond genetic mutations, recent research has shed light on the role of non-genetic plasticity in transient drug tolerance and the acquisition of stable resistance. However, the dynamics of cell state transitions occurring in the adaptation to cancer therapies remain elusive and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell state transitions accompanied by a progressive increase in cell fitness, which we denote the 'resistance continuum'. This cellular adaptation involves a step-wise assembly of gene expression programs and epigenetically reinforced cell states underpinned by phenotypic plasticity, adaptation to stress and metabolic reprogramming. Our results support the notion that EMT/stemness programs, often considered as a proxy for phenotypic plasticity, enable adaptation, rather than a full resistance mechanism. Through systematic genetic perturbations, we identify an acquisition of metabolic dependencies, exposing vulnerabilities that can be potentially exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell state transitions.
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| Overall design |
Kuramochi cells from C (untreated) and adapted (olaparib resistant) T10 and T320 populations were sorted based on their CD24 and CD44 profiles and expanded before being transfected with CRISPR/Cas9 knockout metabolism library. After puromycin selection, cells were collected (initial time point) and expanded by 10 population doublings without drug treatment (C, T10 and T320) and on drug treatment (CD on 1 μM and T320D on 40 μM of olaparib), thus constituting the end time point of the screen. Guide RNAs were sequenced and depletion scores were determined for each sample based on the abundance of gRNAs at the end time point relative to the initial time point.
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| Contributor(s) |
Starvaggi França G, Yanai I |
| Citation missing |
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| Submission date |
Nov 14, 2023 |
| Last update date |
May 22, 2024 |
| Contact name |
Itai Yanai |
| Organization name |
NYU Langone Health
|
| Street address |
435 East. 30th St.
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10016 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE247691 |
Cellular adaptation to cancer therapy along a resistance continuum |
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| Relations |
| BioProject |
PRJNA1040173 |
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