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<p>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 &gt;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<sup>high</sup> 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<sup>–</sup> myofibroblastic CAFs (myCAFs) that were transcriptionally and phenotypically similar to senescent CAFs. Moreover, Wnt9a was demonstrated to be a regulator of senescence in CD34<sup>–</sup> 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.</p>

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Fibroblast hierarchy dynamics during mammary gland morphogenesis and tumorigenesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月11日

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  • Rosa Pascual,
  • Jinming Cheng,
  • Amelia H De Smet,
  • Bianca D Capaldo,
  • Minhsuang Tsai,
  • Somayeh Kordafshari,
  • François Vaillant,
  • Xiaoyu Song,
  • Göknur Giner,
  • Michael J G Milevskiy,
  • Felicity C Jackling,
  • Bhupinder Pal,
  • Toby Dite,
  • Jumana Yousef,
  • Laura F Dagley,
  • Gordon K Smyth,
  • Naiyang Fu,
  • Geoffrey J Lindeman,
  • Yunshun Chen,
  • Jane E Visvader

摘要

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 CD34high 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.