Fibroblast hierarchy dynamics during mammary gland morphogenesis and tumorigenesis
- Author(s)
- Pascual, R; Cheng, J; De Smet, AH; Capaldo, BD; Tsai, M; Kordafshari, S; Vaillant, F; Song, X; Giner, G; Milevskiy, MJG; Jackling, FC; Pal, B; Dite, T; Yousef, J; Dagley, LF; Smyth, GK; Fu, N; Lindeman, GJ; Chen, Y; Visvader, JE;
- Journal Title
- EMBO Journal
- Publication Type
- Online publication before print
- Abstract
- Fibroblasts form a major component of the stroma in normal mammary tissue and breast tumors. Here, we have applied longitudinal single-cell transcriptome profiling of >45,000 fibroblasts in the mouse mammary gland across five different developmental stages and during oncogenesis. In the normal gland, diverse stromal populations were resolved, including lobular-like fibroblasts, committed preadipocytes and adipogenesis-regulatory, as well as cycling fibroblasts in puberty and pregnancy. These specialized cell types appear to emerge from CD34(high) mesenchymal progenitor cells, accompanied by elevated Hedgehog signaling. During late tumorigenesis, heterogeneous cancer-associated fibroblasts (CAFs) were identified in mouse models of breast cancer, including a population of CD34(-) myofibroblastic CAFs (myCAFs) that were transcriptionally and phenotypically similar to senescent CAFs. Moreover, Wnt9a was demonstrated to be a regulator of senescence in CD34(-) myCAFs. These findings reflect a diverse and hierarchically organized stromal compartment in the normal mammary gland that provides a framework to better understand fibroblasts in normal and cancerous states.
- Keywords
- Cancer-Associated Fibroblasts (CAFs); Fibroblasts; Mammary Gland Development; Senescence; Wnt9a
- Department(s)
- Familial Cancer Centre; Medical Oncology
- Publisher's Version
- https://doi.org/10.1038/s44318-025-00422-3
- Open Access at Publisher's Site
https://doi.org/10.1038/s44318-025-00422-3- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-05-15 04:17:37
Last Modified: 2025-05-15 04:17:57