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Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression

Author

Listed:
  • Akikazu Harada

    (The University of Osaka
    The University of Osaka
    The University of Osaka)

  • Yoshiaki Yasumizu

    (The University of Osaka
    The University of Osaka)

  • Takeshi Harada

    (The University of Osaka)

  • Katsumi Fumoto

    (The University of Osaka)

  • Akira Sato

    (The University of Osaka)

  • Natsumi Maehara

    (The University of Osaka)

  • Ryota Sada

    (The University of Osaka
    The University of Osaka
    The University of Osaka)

  • Shinji Matsumoto

    (The University of Osaka
    The University of Osaka)

  • Takashi Nishina

    (Toho University)

  • Kiyoshi Takeda

    (The University of Osaka
    The University of Osaka
    The University of Osaka
    The University of Osaka)

  • Eiichi Morii

    (The University of Osaka)

  • Hisako Kayama

    (The University of Osaka
    The University of Osaka
    The University of Osaka)

  • Akira Kikuchi

    (The University of Osaka
    The University of Osaka
    The University of Osaka)

Abstract

Wnt5a, a representative Wnt ligand that activates the β-catenin-independent pathway, has been shown to promote tumorigenesis. However, it is unclear where Wnt5a is produced and how it affects colon cancer aggressiveness. In this study, we demonstrate that Wnt5a is expressed in fibroblasts near the luminal side of the tumor, and its depletion suppresses mouse colon cancer formation. To characterize the specific fibroblast subtype, a meta-analysis of human and mouse colon fibroblast single-cell RNA-seq data is performed. The results show that Wnt5a is expressed in hypoxia-induced inflammatory fibroblast (InfFib), accompanied by the activation of HIF2. Moreover, Wnt5a maintains InfFib through the suppression of angiogenesis mediated by soluble VEGF receptor1 (Flt1) secretion from endothelial cells, thereby inducing further hypoxia. InfFib also produces epiregulin, which promotes colon cancer growth. Here, we show that Wnt5a acts on endothelial cells, inducing a hypoxic environment that maintains InfFib, thereby contributing to colon cancer progression through InfFib.

Suggested Citation

  • Akikazu Harada & Yoshiaki Yasumizu & Takeshi Harada & Katsumi Fumoto & Akira Sato & Natsumi Maehara & Ryota Sada & Shinji Matsumoto & Takashi Nishina & Kiyoshi Takeda & Eiichi Morii & Hisako Kayama & , 2025. "Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58748-9
    DOI: 10.1038/s41467-025-58748-9
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    References listed on IDEAS

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    1. James A. Stefater III & Ian Lewkowich & Sujata Rao & Giovanni Mariggi & April C. Carpenter & Adam R. Burr & Jieqing Fan & Rieko Ajima & Jeffery D. Molkentin & Bart O. Williams & Marsha Wills-Karp & Je, 2011. "Regulation of angiogenesis by a non-canonical Wnt–Flt1 pathway in myeloid cells," Nature, Nature, vol. 474(7352), pages 511-515, June.
    2. Han Luo & Xuyang Xia & Li-Bin Huang & Hyunsu An & Minyuan Cao & Gyeong Dae Kim & Hai-Ning Chen & Wei-Han Zhang & Yang Shu & Xiangyu Kong & Zhixiang Ren & Pei-Heng Li & Yang Liu & Huairong Tang & Rongh, 2022. "Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Bianca Dumitrascu & Soledad Villar & Dustin G. Mixon & Barbara E. Engelhardt, 2021. "Optimal marker gene selection for cell type discrimination in single cell analyses," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    4. Takashi Nishina & Yutaka Deguchi & Daisuke Ohshima & Wakami Takeda & Masato Ohtsuka & Shigeyuki Shichino & Satoshi Ueha & Soh Yamazaki & Mika Kawauchi & Eri Nakamura & Chiharu Nishiyama & Yuko Kojima , 2021. "Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    5. Jacques Pouysségur & Frédéric Dayan & Nathalie M. Mazure, 2006. "Hypoxia signalling in cancer and approaches to enforce tumour regression," Nature, Nature, vol. 441(7092), pages 437-443, May.
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