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MECHANOBIOLOGY

Softening redox homeostasis in cancer cells

Nature Cell Biology volume 24, pages 133–134 (2022)Cite this article

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Extracellular matrix (ECM) rigidity increases during tumour progression. In a recent study, Romani et al. delineated a connection between ECM stiffness and the redox response of disseminated tumour cells. Their results suggest that soft ECM promotes DRP1-mediated mitochondrial fission and an NRF2-dependent antioxidant response.

In living tissues, cells sense and respond to a wide range of mechanical tensions, including extracellular matrix (ECM) rigidity, fluid shear stress and intercellular compression. Through a variety of mechanotransduction pathways, these mechanical signals can be converted into biochemical signals that trigger the desired cellular response. The tumour stroma is known to increase in stiffness over time as it coevolves with cancer cells2. This is well exemplified by breast tumours, which are often first detected by direct palpation or mammographic density, both of which reflect the increased stiffness of the tumour compared to surrounding tissues3. Moreover, tumour stiffness, as measured by shear wave elastography ultrasound imaging, is highly predictive of patient response to neoadjuvant chemotherapy4 and diminishes significantly upon therapy5. Interestingly, the effects of matrix rigidity on cancer cell behaviour have also been seen in vitro, where cells grown in three-dimensional cultures of greater ECM stiffness display a more invasive phenotype6. Nonetheless, the impact of adhesion-mediated mechanosignaling on freshly disseminated tumour cells had not been explored. Romani et al. have now employed atomic force microscopy to show that the stiffness of early metastatic sites is four times lower than that of late metastatic outgrowths. The authors also propose that the response of a disseminated cancer cell to the soft stroma of a distant organ promotes the chemoresistance of dormant cancer cells1. Indeed, emerging evidence suggests that acellular factors, such as changes in the local ECM composition, may trigger dormant cancer cell awakening and metastasis in experimental models7. However, the molecular processes by which mechanotransduction regulates the properties of dormant cancer cells remain elusive.

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Fig. 1: Mechanosignaling through changes in cell adhesion and matrix stiffness regulates the dynamin-related protein 1 (DRP1)–nuclear factor erythroid 2-related factor 2 (NRF2) axis in disseminated breast cancer cells.

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Authors and Affiliations

  1. Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA

    Justin A. Powers & Iok In Christine Chio

  2. Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA

    Justin A. Powers & Iok In Christine Chio

  3. Department of Chemistry, Columbia University, New York, NY, USA

    Justin A. Powers

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  1. Justin A. Powers
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  2. Iok In Christine Chio
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Correspondence to Iok In Christine Chio.

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Powers, J.A., Chio, I.I.C. Softening redox homeostasis in cancer cells. Nat Cell Biol 24, 133–134 (2022). https://doi.org/10.1038/s41556-022-00845-8

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