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CELL DEATH IN CANCER

Stress response regulates cancer fibroblasts

Nature Cell Biology volume 24, pages 812–814 (2022)Cite this article

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Fibroblasts become activated during wound repair and rapidly return to a ‘resting’ state, and are thus critical for normal tissue homeostasis and tumour development. A new study now reveals an important pro-tumorigenic role for the stress response in cancer-associated fibroblasts that may offer a new opportunity to limit tumour progression.

Focusing on the host ISR, Verginadis et al.5 show that melanoma and pancreatic tumors grew slower and formed fewer and smaller metastases in an Atf4-knockout mouse background resulting in better overall survival. Further characterization of the tumors by single-cell RNA sequencing (scRNA-seq) revealed significant reduction of Acta2- and Pdgfrb- expressing CAFs in Atf4-knockout hosts versus wild-type. Following previously published CAF nomenclature, these CAFs were classified as vascular CAFs (vCAFs) based on their expression profile and the perivascular localization within the tumour2, underscoring the importance not only of expression patterns but also of physical location. It is well known that CAFs can directly promote tumour neovascularization10,11, hence the authors sought to determine whether tumour vasculature had also been impacted in Atf4-knockout hosts. In the melanoma model, marked reduction of microvascular density in tumours from Atf4-knockout hosts corroborated the reduced vascular permeability found in perfusion studies. The authors also showed that αSMA+ (Acta2) vCAFs colocalized with CD31+ endothelial cells and the reduction in type I collagen expression observed in vCAFs by scRNA-seq was restricted to perivascular areas. Finally, co-implantation studies of melanoma cells with Atf4-knockout or wild-type dermal fibroblasts revealed that the lack of Atf4 within CAFs was sufficient to reduce tumour growth. Similarly, conditional mice that lacked Atf4 expression specifically in fibroblasts showed decreased tumour growth in comparison to wild-type mice when inoculated with B16F10 melanoma cells.

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Fig. 1: ATF4 is the executioner transcription factor of ISR signalling.

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Authors and Affiliations

  1. Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA

    Douglas V. Faget & Sheila A. Stewart

  2. Department of Medicine, Washington University School of Medicine, St Louis, MO, USA

    Sheila A. Stewart

  3. Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA

    Sheila A. Stewart

  4. ICCE Institute, Washington University School of Medicine, St Louis, MO, USA

    Sheila A. Stewart

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  1. Douglas V. Faget
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  2. Sheila A. Stewart
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Correspondence to Sheila A. Stewart.

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Faget, D.V., Stewart, S.A. Stress response regulates cancer fibroblasts. Nat Cell Biol 24, 812–814 (2022). https://doi.org/10.1038/s41556-022-00930-y

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