Preexisting senescent fibroblasts in the aged bladder create a tumor-permissive niche through CXCL12 secretion
Aging is a major risk factor for cancer, but the precise mechanism by which aging promotes carcinogenesis remains largely unknown. Here, using genetically modified mouse models, we show that p16<sup>high</sup> senescent (p16<sup>h</sup>-sn) fibroblasts accumulate with age, constitute inflammatory cancer-associated fibroblasts (CAFs) and promote tumor growth in bladder cancer models. Single-cell RNA sequencing of fibroblasts from aged mice revealed higher expression of the C-X-C motif chemokine 12 gene (Cxcl12) in p16<sup>h</sup>-sn fibroblasts than in p16<sup>low</sup> fibroblasts. Elimination of p16<sup>h</sup>-sn cells or inhibition of CXCL12 signaling notebly suppressed bladder tumor growth in vivo. We identified high expression levels of SMOC2, GUCY1A1 (GUCY1A3), CXCL12, CRISPLD2, GAS1 and LUM as a signature of p16<sup>h</sup>-sn CAFs in humans and mice, which was associated with age and poor prognosis in patients with advanced and nonadvanced bladder cancer. Here we show that p16<sup>h</sup>-sn fibroblasts in the aged bladder create a cancer-permissive niche and promote tumor growth by secreting CXCL12.
Authors
- Emina Kayama (ORCID: https://orcid.org/0009-0004-6647-1945)
- Kiyoshi Yamaguchi (ORCID: https://orcid.org/0000-0003-2113-4369)
- Yoichi Furukawa (ORCID: https://orcid.org/0000-0003-0462-8631)
- Yoshikazu Johmura (ORCID: https://orcid.org/0000-0002-6812-9607)
- Makoto Nakanishi (ORCID: https://orcid.org/0000-0002-6707-3584)
- Eigo Shimizu (ORCID: https://orcid.org/0000-0002-2486-2321)
- Satotaka Omori (ORCID: https://orcid.org/0000-0002-0423-7289)
- Seira Hatakeyama (ORCID: https://orcid.org/0000-0002-5726-3317)
- Satoru Meguro (ORCID: https://orcid.org/0000-0003-2179-5028)
- Satoshi Yamazaki (ORCID: https://orcid.org/0000-0003-4249-3854)
- Satoshi Kawakami (ORCID: https://orcid.org/0000-0003-2627-9444)
- Teh‐Wei Wang
- Shota Tanimoto
- Y Okamura (ORCID: https://orcid.org/0000-0002-0489-545X)
- Seiji Hoshi (ORCID: https://orcid.org/0000-0003-1545-1827)
- Seiya Imoto (ORCID: https://orcid.org/0000-0002-2989-308X)
- Yoshiyuki Kojima (ORCID: https://orcid.org/0000-0001-8000-0868)
Institutions
- Kanazawa University (JP)
- Broad Institute (US)
- Fukushima Medical University (JP)
- University of Tsukuba (JP)
- Tokyo University of Science (JP)
- The Cancer Institute Hospital (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- Nature Aging
- Published
- 2024-09-09
- DOI
- https://doi.org/10.1038/s43587-024-00704-1
- Citations
- 26
- Primary Topic
- Bladder and Urothelial Cancer Treatments
- Type
- article
- Field-Weighted Citation Impact
- 14.89
Funders
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science