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Molecular mechanisms altering cell identity in cancer

Oncogene volume 44, pages 2117–2126 (2025) Cite this article

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Abstract

Intrinsic and extrinsic factors influence cancer cell identity throughout its lifespan. During tumor progression and metastasis formation, cancer cells are exposed to different environmental stimuli, resulting in a stepwise cellular reprogramming. Similar stepwise changes of cell identity have been shown as a major consequence of cancer treatment, as cells are exposed to extracellular stress that can result in the establishment of subpopulations exhibiting different epigenetic and transcriptional patterns, indicating a rapid adaptation mechanism of cellular identity by extrinsic stress factors. Both mechanisms, tumor progression-mediated changes and therapy response, rely on signaling pathways affecting the epigenetic and subsequent transcriptional landscape, which equip the cells with mechanisms for survival and tumor progression. These non-genetic alterations are propagated to the daughter cells, indicating a need for successful information propagation and transfer to the daughter generations, thereby allowing for a stepwise adaptation to environmental cues. However, the exact mechanisms how these cell identity changes are occurring, which context-specific mechanisms are behind and how this can be exploited for future therapeutic interventions is not yet fully understood and exploited. In this review, we discuss the current knowledge on cell identity maintenance mechanisms intra- and intergenerational in development and disease and how these mechanisms are altered in cancer. We will as well address how cancer treatment might target these properties.

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Fig. 1: Definition of cell identity.
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Fig. 2: Mitotic bookmarking.
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Fig. 3: Examples of mitotic bookmarking alterations in cancer.
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Acknowledgements

The Beyes Lab is supported by the Robert Bosch Stiftung GmbH. Work in the Zippo Lab is supported by the AIRC foundation (IG 2019-22911).

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Authors and Affiliations

  1. Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy

    Alessio Zippo

  2. Robert Bosch Center for Tumor Diseases (RBCT), Stuttgart, Germany

    Sven Beyes

Authors
  1. Alessio Zippo
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  2. Sven Beyes
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Initial idea and conceptualization: SB and AZ; writing original draft, and figure preparation: SB; critical revisions: AZ

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Correspondence to Alessio Zippo or Sven Beyes.

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Zippo, A., Beyes, S. Molecular mechanisms altering cell identity in cancer. Oncogene 44, 2117–2126 (2025). https://doi.org/10.1038/s41388-025-03314-2

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