Thursday, April 16, 2026
No menu items!
HomeNatureA mechanism for adaptive genome regulation in cancer

A mechanism for adaptive genome regulation in cancer

  • Llinás, R. R. The contribution of Santiago Ramón y Cajal to functional neuroscience. Nat. Rev. Neurosci. 4, 77–80 (2003).

    Article 
    PubMed 

    Google Scholar
     

  • McCulloch, E. A. & Till, J. E. Perspectives on the properties of stem cells. Nat. Med. 11, 1026–1028 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kumar, T. et al. A spatially resolved single-cell genomic atlas of the adult human breast. Nature 620, 181–191 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Sikkema, L. et al. An integrated cell atlas of the lung in health and disease. Nat. Med. 29, 1563–1577 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Barkley, D. et al. Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment. Nat. Genet. 54, 1192–1201 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gavish, A. et al. Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours. Nature 618, 598–606 (2023). The Barkley et al. and Gavish et al. studies define meta programs of gene expression across many tumour types, showing that cancer cell states tend to be shared across tumours.

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Gargiulo, G., Serresi, M. & Marine, J.-C. Cell states in cancer: drivers, passengers, and trailers. Cancer Discov. 14, 610–614 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zeng, H. What is a cell type and how to define it? Cell 185, 2739–2755 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Velten, L. et al. Human haematopoietic stem cell lineage commitment is a continuous process. Nat. Cell Biol. 19, 271–281 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pastushenko, I. et al. Identification of the tumour transition states occurring during EMT. Nature 556, 463–468 (2018).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Ladewig, J., Koch, P. & Brüstle, O. Leveling Waddington: the emergence of direct programming and the loss of cell fate hierarchies. Nat. Rev. Mol. Cell Biol. 14, 225–236 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • West-Eberhard, M. J. Developmental Plasticity and Evolution (Oxford Univ. Press, 2003).

  • Levis, N. A. & Pfennig, D. W. Evaluating ‘plasticity-first’ evolution in nature: key criteria and empirical approaches. Trends Ecol. Evol. 31, 563–574 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Frank, S. A. & Yanai, I. The origin of novel traits in cancer. Trends Cancer 10, 880–892 (2024). This article argues that novel traits in cancer can originate through initially non-heritable phenotypic variation, challenging the classic gene-centric view.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Frank, S. A. How cancer arises: genetics releases, plasticity creates, genetics stabilizes. Proc. Natl Acad. Sci. USA 122, e2505377122 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Frank, S. A. & Rosner, M. R. Nonheritable cellular variability accelerates the evolutionary processes of cancer. PLoS Biol. 10, e1001296 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gupta, P. B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kaern, M., Elston, T. C., Blake, W. J. & Collins, J. J. Stochasticity in gene expression: from theories to phenotypes. Nat. Rev. Genet. 6, 451–464 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kreso, A. et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 339, 543–548 (2013).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Marsolier, J. et al. H3K27me3 conditions chemotolerance in triple-negative breast cancer. Nat. Genet. 54, 459–468 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Oren, Y. et al. Cycling cancer persister cells arise from lineages with distinct programs. Nature 596, 576–582 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Goyal, Y. et al. Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells. Nature 620, 651–659 (2023). This paper shows that genetically identical cancer cells can give rise to distinct drug-resistant phenotypes, which are largely predetermined by intrinsic cell-state differences before treatment.

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Shaffer, S. M. et al. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature 546, 431–435 (2017). This landmark study demonstrates that non-genetic drug resistance arises from rare cells that transiently express resistance-associated genes.

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Rosano, D. et al. Long-term multimodal recording reveals epigenetic adaptation routes in dormant breast cancer cells. Cancer Discov. 14, 866–889 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rehman, S. K. et al. Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell 184, 226–242.e21 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dhimolea, E. et al. An embryonic diapause-like adaptation with suppressed myc activity enables tumor treatment persistence. Cancer Cell 39, 240–256.e11 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hastings, J. F. et al. Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma. Sci. Adv. 9, eabp8314 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010). This seminal work discovers a new mechanism of drug resistance, in which cancer cells can transiently and reversibly enter a drug-tolerant state through non-genetic changes.

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Russo, M. et al. Cancer drug-tolerant persister cells: from biological questions to clinical opportunities. Nat. Rev. Cancer 24, 694–717 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Marine, J.-C., Dawson, S.-J. & Dawson, M. A. Non-genetic mechanisms of therapeutic resistance in cancer. Nat. Rev. Cancer 20, 743–756 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brock, A., Chang, H. & Huang, S. Non-genetic heterogeneity — a mutation-independent driving force for the somatic evolution of tumours. Nat. Rev. Genet. 10, 336–342 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pisco, A. O. et al. Non-Darwinian dynamics in therapy-induced cancer drug resistance. Nat. Commun. 4, 2467 (2013).

    Article 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Tong, X. et al. Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer. Cancer Cell 42, 413–428.e7 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chan, J. M. et al. Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling. Science 377, 1180–1191 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Tsoi, J. et al. Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress. Cancer Cell 33, 890–904.e5 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shibue, T. & Weinberg, R. A. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 14, 611–629 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Oliveira, E. A. et al. Epigenetic heritability of cell plasticity drives cancer drug resistance through a one-to-many genotype-to-phenotype paradigm. Cancer Res. 85, 2921–2938 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Marusyk, A., Janiszewska, M. & Polyak, K. Intratumor heterogeneity: the Rosetta stone of therapy resistance. Cancer Cell 37, 471–484 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Marjanovic, N. D. et al. Emergence of a high-plasticity cell state during lung cancer evolution. Cancer Cell 38, 229–246.e13 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mzoughi, S. et al. Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer. Nat. Genet. 57, 402–412 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moorman, A. et al. Progressive plasticity during colorectal cancer metastasis. Nature 637, 947–954 (2025). This study uncovers extreme phenotypic plasticity driving metastasis in colorectal cancer, in which intestinal cells undergo dedifferentiation through a highly plastic oncofetal state and adopt squamous and neuroendocrine-like states.

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • França, G. S. et al. Cellular adaptation to cancer therapy along a resistance continuum. Nature 631, 876–883 (2024). This work introduced the concept of the ‘resistance continuum’, revealing that drug resistance emerges through progressive adaptive cell-state transitions towards increased fitness, underpinned by phenotypic plasticity and chromatin reprogramming for stress response.

    Article 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Vander Velde, R. et al. Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures. Nat. Commun. 11, 2393 (2020). This work introduced the notion that resistance to targeted therapy arises through a gradual process of adaptation explained by both genetic and non-genetic mechanisms.

    Article 
    ADS 

    Google Scholar
     

  • Li, J. et al. AP-1 mediates cellular adaptation and memory formation. Nat. Commun. https://doi.org/10.1038/s41467-026-70862-w (2026). This study reveals that melanoma cells develop therapy resistance by forming AP-1-dependent cellular memories, suggesting heritable adaptive genome reprogramming.

  • Fennell, K. A. et al. Non-genetic determinants of malignant clonal fitness at single-cell resolution. Nature 601, 125–131 (2022).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Morgan, D., Gardner, A. L. & Brock, A. Lineage tracing reveals clone-specific responses to doxorubicin in triple-negative breast cancer. Preprint at bioRxiv https://doi.org/10.1101/2025.03.18.643980 (2025).

  • Lee, P., Chandel, N. S. & Simon, M. C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat. Rev. Mol. Cell Biol. 21, 268–283 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jacob, F. & Monod, J. Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3, 318–356 (1961).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Davidson, E. H. Emerging properties of animal gene regulatory networks. Nature 468, 911–920 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Chalancon, G. et al. Interplay between gene expression noise and regulatory network architecture. Trends Genet. 28, 221–232 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Levine, M. & Davidson, E. H. Gene regulatory networks for development. Proc. Natl Acad. Sci. USA 102, 4936–4942 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Braun, E. The unforeseen challenge: from genotype-to-phenotype in cell populations. Rep. Prog. Phys. 78, 036602 (2015). This work proposes a unifying framework in which cell states can emerge from exploratory dynamics of gene regulation, offering a transformative view of how cells can adapt to unfamiliar environmental conditions.

    Article 
    PubMed 
    ADS 

    Google Scholar
     

  • Shomar, A., Barak, O. & Brenner, N. Cancer progression as a learning process. iScience 25, 103924 (2022). This paper proposes that cellular adaptation in cancer arises through a process analogous to cellular learning facilitated by transcription factors that work as regulatory hubs.

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Freddolino, L., Yang, J., Momen-Roknabadi, A. & Tavazoie, S. Stochastic tuning of gene expression enables cellular adaptation in the absence of pre-existing regulatory circuitry. eLife 7, e31867 (2018). This study proposed a stochastic tuning mechanism by which cells adapt to novel environments through fitness-driven adjustments of individual gene expression.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Momen-Roknabadi, A., Oikonomou, P. & Tavazoie, S. Adaptation by stochastic tuning of gene expression in mammalian cells. Preprint at bioRxiv https://doi.org/10.1101/2025.05.07.651953 (2025).

  • Schreier, H. I., Soen, Y. & Brenner, N. Exploratory adaptation in large random networks. Nat. Commun. 8, 14826 (2017).

    Article 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Baron, M. et al. The stress-like cancer cell state is a consistent component of tumorigenesis. Cell Syst 11, 536–546.e7 (2020). This study describes a conserved stress-like cancer cell state in tumorigenesis, characterized by enhanced tumour seeding and drug tolerance.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vihervaara, A., Duarte, F. M. & Lis, J. T. Molecular mechanisms driving transcriptional stress responses. Nat. Rev. Genet. 19, 385–397 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Greenberg, M. E. & Ziff, E. B. Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature 311, 433–438 (1984).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Baudre, L. et al. Characterization of drug-tolerant persister cells in triple-negative breast cancer identifies a shared persistence program across treatments and patients. Cancer Res. 86, 802–817 (2026).

  • Diao, S. et al. Lineage plasticity of the integrated stress response is a hallmark of cancer evolution. Preprint at bioRxiv https://doi.org/10.1101/2025.02.10.637516 (2025).

  • D’Urso, A. & Brickner, J. H. Mechanisms of epigenetic memory. Trends Genet. 30, 230–236 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Owen, J. A., Osmanović, D. & Mirny, L. Design principles of 3D epigenetic memory systems. Science 382, eadg3053 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Espinosa-Martínez, M., Alcázar-Fabra, M. & Landeira, D. The molecular basis of cell memory in mammals: the epigenetic cycle. Sci. Adv. 10, eadl3188 (2024).

    Article 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Tian, C. et al. Impaired histone inheritance promotes tumor progression. Nat. Commun. 14, 3429 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Zhao, S., Allis, C. D. & Wang, G. G. The language of chromatin modification in human cancers. Nat. Rev. Cancer 21, 413–430 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shaulian, E. & Karin, M. AP-1 as a regulator of cell life and death. Nat. Cell Biol. 4, E131–E136 (2002). This seminal review discusses the key functional and mechanistic properties of the AP-1 family members.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Eferl, R. & Wagner, E. F. AP-1: a double-edged sword in tumorigenesis. Nat. Rev. Cancer 3, 859–868 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chiu, R. et al. The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell 54, 541–552 (1988).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cohen, D. R., Ferreira, P. C., Gentz, R., Franza, B. R. Jr & Curran, T. The product of a fos-related gene, fra-1, binds cooperatively to the AP-1 site with Jun: transcription factor AP-1 is comprised of multiple protein complexes. Genes Dev. 3, 173–184 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • van Dam, H. & Castellazzi, M. Distinct roles of Jun: Fos and Jun: ATF dimers in oncogenesis. Oncogene 20, 2453–2464 (2001).

    Article 
    PubMed 

    Google Scholar
     

  • Bejjani, F., Evanno, E., Zibara, K., Piechaczyk, M. & Jariel-Encontre, I. The AP-1 transcriptional complex: local switch or remote command? Biochim. Biophys. Acta Rev. Cancer 1872, 11–23 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Seo, J. et al. AP-1 subunits converge promiscuously at enhancers to potentiate transcription. Genome Res. 31, 538–550 (2021). This study maps the genome-wide binding of AP-1 subunits and reveals promiscuous binding at genomic hotspots, suggesting this is key for regulating cell-type-specific gene expression and environmental responses.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vierbuchen, T. et al. AP-1 transcription factors and the BAF complex mediate signal-dependent enhancer selection. Mol. Cell 68, 1067–1082.e12 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou, H. et al. Frequency and distribution of AP-1 sites in the human genome. DNA Res. 12, 139–150 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fonseca, G. J. et al. Diverse motif ensembles specify non-redundant DNA binding activities of AP-1 family members in macrophages. Nat. Commun. 10, 414 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Hess, J., Angel, P. & Schorpp-Kistner, M. AP-1 subunits: quarrel and harmony among siblings. J. Cell Sci. 117, 5965–5973 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Markov, G. J. et al. AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency. Proc. Natl Acad. Sci. USA 118, e2104841118 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Comandante-Lou, N., Baumann, D. G. & Fallahi-Sichani, M. AP-1 transcription factor network explains diverse patterns of cellular plasticity in melanoma cells. Cell Rep. 40, 111147 (2022). This study reveals that the AP-1 transcription factor network determines cellular states in melanoma, showing that the balance among its subunits governs differentiation states and therapy response.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kuonen, F. et al. c-FOS drives reversible basal to squamous cell carcinoma transition. Cell Rep. 37, 109774 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Li, Y. et al. Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer. Nat. Cancer 2, 49–65 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Eckert, L. et al. Biochemically plausible models of habituation for single-cell learning. Curr. Biol. 34, 5646–5658.e3 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Karin, M. The regulation of AP-1 activity by mitogen-activated protein kinases. J. Biol. Chem. 270, 16483–16486 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Karin, M., Liu, Z. G. & Zandi, E. AP-1 function and regulation. Curr. Opin. Cell Biol. 9, 240–246 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Boyle, W. J. et al. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell 64, 573–584 (1991).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Reddy, C. E. et al. Multisite phosphorylation of c-Jun at threonine 91/93/95 triggers the onset of c-Jun pro-apoptotic activity in cerebellar granule neurons. Cell Death Dis. 4, e852 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pulverer, B. J., Kyriakis, J. M., Avruch, J., Nikolakaki, E. & Woodgett, J. R. Phosphorylation of c-Jun mediated by MAP kinases. Nature 353, 670–674 (1991).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Waudby, C. A. et al. An intrinsic temporal order of c-JUN N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment. Nat. Commun. 13, 6133 (2022). This study reveals that multisite phosphorylation of JUN by JNK occurs with distinct temporal kinetics, suggesting a mechanism that switches JUN between repressive and activating states.

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Degefu, Y. N., Bujnowska, M., Baumann, D. G. & Fallahi-Sichani, M. Cell state plasticity emerging from co-regulated, competitive, and configurable interactions within the AP-1 network. Preprint at bioRxiv https://doi.org/10.1101/2025.11.06.686987 (2025). This study examines AP-1 as a configurable, competitive network whose dimerization dynamics encode discrete cell states and drive melanoma plasticity and therapy resistance.

  • Biddie, S. C. et al. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol. Cell 43, 145–155 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wolf, B. K. et al. Cooperation of chromatin remodeling SWI/SNF complex and pioneer factor AP-1 shapes 3D enhancer landscapes. Nat. Struct. Mol. Biol. 30, 10–21 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kamei, Y. et al. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85, 403–414 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Naik, S. et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550, 475–480 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Naik, S. & Fuchs, E. Inflammatory memory and tissue adaptation in sickness and in health. Nature 607, 249–255 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Larsen, S. B. et al. Establishment, maintenance, and recall of inflammatory memory. Cell Stem Cell 28, 1758–1774.e8 (2021). This study uncovers how inflammatory memory is established and recalled in epidermal stem cells, showing the role of AP-1 in establishing chromatin memory for faster responses to subsequent stresses.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nagaraja, S. et al. Epigenetic memory of colitis promotes tumour growth. Nature https://doi.org/10.1038/s41586-026-10258-4 (2026).

  • Benhar, M., Engelberg, D. & Levitzki, A. ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep. 3, 420–425 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Savy, T., Flanders, L., Karpanasamy, T., Sun, M. & Gerlinger, M. Cancer evolution: from Darwin to the extended evolutionary synthesis. Trends Cancer 11, 204–215 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Suski, J. M., Braun, M., Strmiska, V. & Sicinski, P. Targeting cell-cycle machinery in cancer. Cancer Cell 39, 759–778 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sawyers, C. Targeted cancer therapy. Nature 432, 294–297 (2004).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Groelly, F. J., Fawkes, M., Dagg, R. A., Blackford, A. N. & Tarsounas, M. Targeting DNA damage response pathways in cancer. Nat. Rev. Cancer 23, 78–94 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, L. J. et al. Cancer plasticity: the role of mRNA translation. Trends Cancer 7, 134–145 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Faubert, B., Solmonson, A. & DeBerardinis, R. J. Metabolic reprogramming and cancer progression. Science 368, eaaw5473 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Geffen, Y. et al. Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation. Cell 186, 3945–3967.e26 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Poulikakos, P. I. et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480, 387–390 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Harmange, G. et al. Disrupting cellular memory to overcome drug resistance. Nat. Commun. 14, 7130 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Boumahdi, S. & de Sauvage, F. J. The great escape: tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Discov. 19, 39–56 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Liau, B. B. et al. Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance. Cell Stem Cell 20, 233–246.e7 (2017).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Zawistowski, J. S. et al. Enhancer remodeling during adaptive bypass to MEK inhibition is attenuated by pharmacologic targeting of the P-TEFb complex. Cancer Discov. 7, 302–321 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Falkenberg, K. J. & Johnstone, R. W. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discov. 13, 673–691 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lasko, L. M. et al. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature 550, 128–132 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Soragni, A. et al. Acquired resistance in cancer: towards targeted therapeutic strategies. Nat. Rev. Cancer 25, 613–633 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yao, C. D. et al. AP-1 and TGFβ cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma. Nat. Commun. 11, 5079 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Wagner, E. F. & Nebreda, A. R. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat. Rev. Cancer 9, 537–549 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pei, G. et al. Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer. Nature 642, 212–221 (2025).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • de Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Hunter, M. V. et al. Mechanical confinement governs phenotypic plasticity in melanoma. Nature 647, 517–527 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Quintanilla, M., Brown, K., Ramsden, M. & Balmain, A. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322, 78–80 (1986).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Bala, P. et al. Aberrant cell state plasticity mediated by developmental reprogramming precedes colorectal cancer initiation. Sci. Adv. 9, eadf0927 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Balmain, A. The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk. Nat. Genet. 52, 1139–1143 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baggiolini, A. et al. Developmental chromatin programs determine oncogenic competence in melanoma. Science 373, eabc1048 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, H., Able, A. J. & Able, J. A. Priming crops for the future: rewiring stress memory. Trends Plant Sci. 27, 699–716 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nadal-Ribelles, M. et al. Transcriptional heterogeneity shapes stress-adaptive responses in yeast. Nat. Commun. 16, 2631 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Moye-Rowley, W. S., Harshman, K. D. & Parker, C. S. Yeast YAP1 encodes a novel form of the Jun family of transcriptional activator proteins. Genes Dev. 3, 283–292 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stern, S., Dror, T., Stolovicki, E., Brenner, N. & Braun, E. Genome-wide transcriptional plasticity underlies cellular adaptation to novel challenge. Mol. Syst. Biol. 3, 106 (2007).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Griffith, E. C., West, A. E. & Greenberg, M. E. Neuronal enhancers fine-tune adaptive circuit plasticity. Neuron 112, 3043–3057 (2024). This perspective article links AP-1 with the dynamics of activity-dependent enhancers in fine-tuning neuronal plasticity.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pettit, N. L., Yap, E.-L., Greenberg, M. E. & Harvey, C. D. Fos ensembles encode and shape stable spatial maps in the hippocampus. Nature 609, 327–334 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Santoni, G. et al. Chromatin plasticity predetermines neuronal eligibility for memory trace formation. Science 385, eadg9982 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Raivich, G. et al. The AP-1 transcription factor c-Jun is required for efficient axonal regeneration. Neuron 43, 57–67 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375–388 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sarate, R. M. et al. Dynamic regulation of tissue fluidity controls skin repair during wound healing. Cell 187, 5298–5315.e19 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wagner, G. P., Erkenbrack, E. M. & Love, A. C. Stress-induced evolutionary innovation: a mechanism for the origin of cell types. Bioessays 41, e1800188 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Love, A. C. & Wagner, G. P. Co-option of stress mechanisms in the origin of evolutionary novelties. Evolution 76, 394–413 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Peng, J., Wang, B.-J., Svetec, N. & Zhao, L. Gene regulatory networks and essential transcription factors for de novo-originated genes. Nat. Ecol. Evol. 9, 1487–1498 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Patel, A. S. & Yanai, I. A developmental constraint model of cancer cell states and tumor heterogeneity. Cell 187, 2907–2918 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jacob, F. Evolution and tinkering. Science 196, 1161–1166 (1977).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Malnic, B., Hirono, J., Sato, T. & Buck, L. B. Combinatorial receptor codes for odors. Cell 96, 713–723 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tonegawa, S. Somatic generation of antibody diversity. Nature 302, 575–581 (1983).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Barrangou, R. et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science 315, 1709–1712 (2007).

    Article 
    CAS 
    PubMed 
    ADS 

    Google Scholar
     

  • Perkins, N. D. The diverse and complex roles of NF-κB subunits in cancer. Nat. Rev. Cancer 12, 121–132 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hsiung, C. C.-S. et al. Engineered CRISPR–Cas12a for higher-order combinatorial chromatin perturbations. Nat. Biotechnol. 43, 369–383 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fu, X. et al. A foundation model of transcription across human cell types. Nature 637, 965–973 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Neftel, C. et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell 178, 835–849.e21 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Karras, P. et al. A cellular hierarchy in melanoma uncouples growth and metastasis. Nature 610, 190–198 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    ADS 

    Google Scholar
     

  • Becker, W. R. et al. Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer. Nat. Genet. 54, 985–995 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tirosh, I. & Suva, M. L. Cancer cell states: lessons from ten years of single-cell RNA-sequencing of human tumors. Cancer Cell 42, 1497–1506 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • RELATED ARTICLES

    Most Popular

    Recent Comments