Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression
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 n...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58748-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850145181275258880 |
|---|---|
| author | Akikazu Harada Yoshiaki Yasumizu Takeshi Harada Katsumi Fumoto Akira Sato Natsumi Maehara Ryota Sada Shinji Matsumoto Takashi Nishina Kiyoshi Takeda Eiichi Morii Hisako Kayama Akira Kikuchi |
| author_facet | Akikazu Harada Yoshiaki Yasumizu Takeshi Harada Katsumi Fumoto Akira Sato Natsumi Maehara Ryota Sada Shinji Matsumoto Takashi Nishina Kiyoshi Takeda Eiichi Morii Hisako Kayama Akira Kikuchi |
| author_sort | Akikazu Harada |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3f2d8f45819946e6953881838d1e1bfb |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3f2d8f45819946e6953881838d1e1bfb2025-08-20T02:28:09ZengNature PortfolioNature Communications2041-17232025-04-0116112410.1038/s41467-025-58748-9Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progressionAkikazu Harada0Yoshiaki Yasumizu1Takeshi Harada2Katsumi Fumoto3Akira Sato4Natsumi Maehara5Ryota Sada6Shinji Matsumoto7Takashi Nishina8Kiyoshi Takeda9Eiichi Morii10Hisako Kayama11Akira Kikuchi12Center for Infectious Disease Education and Research (CiDER), The University of OsakaInstitute for Open and Transdisciplinary Research Initiatives (OTRI), The University of OsakaDepartment of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of OsakaDepartment of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of OsakaDepartment of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of OsakaDepartment of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of OsakaCenter for Infectious Disease Education and Research (CiDER), The University of OsakaInstitute for Open and Transdisciplinary Research Initiatives (OTRI), The University of OsakaDepartment of Biochemistry, Faculty of Medicine, Toho UniversityCenter for Infectious Disease Education and Research (CiDER), The University of OsakaDepartment of Pathology, Graduate School of Medicine, The University of OsakaLaboratory of Mucosal Immunology, WPI Frontier Immunology Research Center, The University of OsakaCenter for Infectious Disease Education and Research (CiDER), The University of OsakaAbstract 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.https://doi.org/10.1038/s41467-025-58748-9 |
| spellingShingle | Akikazu Harada Yoshiaki Yasumizu Takeshi Harada Katsumi Fumoto Akira Sato Natsumi Maehara Ryota Sada Shinji Matsumoto Takashi Nishina Kiyoshi Takeda Eiichi Morii Hisako Kayama Akira Kikuchi Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression Nature Communications |
| title | Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression |
| title_full | Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression |
| title_fullStr | Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression |
| title_full_unstemmed | Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression |
| title_short | Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression |
| title_sort | hypoxia induced wnt5a secreting fibroblasts promote colon cancer progression |
| url | https://doi.org/10.1038/s41467-025-58748-9 |
| work_keys_str_mv | AT akikazuharada hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT yoshiakiyasumizu hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT takeshiharada hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT katsumifumoto hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT akirasato hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT natsumimaehara hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT ryotasada hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT shinjimatsumoto hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT takashinishina hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT kiyoshitakeda hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT eiichimorii hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT hisakokayama hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression AT akirakikuchi hypoxiainducedwnt5asecretingfibroblastspromotecoloncancerprogression |