ArticleCancer research2025
Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm.
Article in Cancer research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
29 citing papers in PubMed.
- Review
- Heterogeneity in cancer: molecular mechanisms and therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- A guide to understanding tumour evolution through the lens of population genetics.Nature reviews. Cancer · 2026Review
- A single-cell lens into the co-evolution of genotypes and phenotypes in cancer.Nature reviews. Cancer · 2026Review
- Drug-tolerant persister cells use conserved adaptive transcriptional programs.Translational cancer research · 2026Article
- Clonal memory of cell division in humans diverges between healthy haematopoiesis and acute myeloid leukaemia.Nature communications · 2026Article
- Plasticity of Non-Apoptotic Residual Tumor Cells After Neoadjuvant Immunochemotherapy: Epigenetic and Microenvironmental Determinants.Biomolecules · 2026Review
- Cancer Heterogeneity and Cancer Cell Plasticity: Molecular Mechanisms and Precision Therapy.MedComm · 2026Review
- Multidrug resistance in cancer: current understandings and future perspective.Molecular biomedicine · 2026Review
- Review
- The Shape-Shifting Myeloma: Adaptive Plasticity as a Hallmark of Relapse and Refractoriness.Cancers · 2026Review
- Therapy-Driven Molecular Evolution of Bladder Cancer: Roles of Cellular Plasticity and Tumor Microenvironment.International journal of molecular sciences · 2026Review
- Deconstructing cancer in 3D: models, mechanisms, and personalized solutions.Molecular cancer · 2026Review
- Charting single-cell lineages with synthetic and natural barcodes.Nature reviews. Genetics · 2026Review
- Transforming tumor microenvironments: nanotechnology and gene therapy in cellular signaling and epigenetic insight into chemo-resistance.Journal of experimental & clinical cancer research : CR · 2026Review
- From undruggable to degradable: A deep learning-enabled framework for precision orthopaedic protein degradation.Journal of orthopaedic translation · 2026Review
- Epigenetic modifications in cancer drug resistance: molecular mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- The role of small extracellular vesicles in ovarian cancer drug resistance: from bench clues to clinical implications.Journal of ovarian research · 2026Review
- Review
- Strength through diversity: how cancers thrive when clones cooperate.Molecular oncology · 2026Review
Corrections and comments
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Authors and funding
20 authors.
Funding
Abstract
Cancer drug resistance is multifactorial, driven by heritable (epi)genetic changes but also by phenotypic plasticity. In this study, we dissected the drivers of resistance by perturbing organoids derived from patients with colorectal cancer longitudinally with drugs in sequence. Combined longitudinal lineage tracking, single-cell multiomics analysis, evolutionary modeling, and machine learning revealed that different targeted drugs select for distinct subclones, supporting rationally designed drug sequences. The cellular memory of drug resistance was encoded as a heritable epigenetic configuration from which multiple transcriptional programs could run, supporting a one-to-many (epi)genotype-to-phenotype map that explains how clonal expansions and plasticity manifest together. This epigenetic landscape may ensure drug-resistant subclones can exhibit distinct phenotypes in changing environments while still preserving the cellular memory encoding for their selective advantage. Chemotherapy resistance was instead entirely driven by transient phenotypic plasticity rather than stable clonal selection. Inducing further chromosomal instability before drug application changed clonal evolution but not convergent transcriptional programs. Collectively, these data show how genetic and epigenetic alterations are selected to engender a "permissive epigenome" that enables phenotypic plasticity. SIGNIFICANCE: Drug resistance is driven by genetic-epigenetic memory that enables cancer cells to adopt multiple phenotypic states depending on environmental conditions, supporting integration of evolutionary principles into biomarker discovery and personalized treatment strategies. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.