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Fibroblast hierarchy dynamics during mammary gland morphogenesis and tumorigenesis.

Rosa Pascual1,2, Jinming Cheng1,2,3, Amelia H De Smet1,2

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Summary

This study reveals diverse fibroblast populations in the normal mammary gland and identifies cancer-associated fibroblasts (CAFs) during tumor development. Understanding these stromal cells is key to normal and cancerous states.

Keywords:
Cancer-Associated Fibroblasts (CAFs)FibroblastsMammary Gland DevelopmentSenescenceWnt9a

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Area of Science:

  • Cell Biology
  • Developmental Biology
  • Oncology

Background:

  • Fibroblasts are crucial stromal components in mammary tissue and tumors.
  • Understanding fibroblast heterogeneity is vital for comprehending mammary gland development and cancer.

Purpose of the Study:

  • To profile fibroblast heterogeneity during mammary gland development and oncogenesis using single-cell transcriptomics.
  • To identify distinct fibroblast subpopulations and their developmental origins and roles in cancer.

Main Methods:

  • Longitudinal single-cell transcriptome profiling of over 45,000 fibroblasts.
  • Analysis across five developmental stages and during oncogenesis in mouse models.
  • Investigation of cell type emergence from mesenchymal progenitor cells and signaling pathways.

Main Results:

  • Resolution of diverse stromal fibroblast populations in the normal gland, including preadipocytes and cycling fibroblasts.
  • Identification of specialized fibroblasts originating from CD34high mesenchymal progenitor cells with elevated Hedgehog signaling.
  • Characterization of heterogeneous cancer-associated fibroblasts (CAFs), including CD34- myofibroblastic CAFs (myCAFs) resembling senescent CAFs.
  • Wnt9a identified as a regulator of senescence in CD34- myCAFs.

Conclusions:

  • The normal mammary gland harbors a diverse, hierarchically organized stromal compartment.
  • Fibroblast heterogeneity plays significant roles in both normal mammary gland function and breast cancer progression.
  • These findings provide a framework for understanding fibroblast biology in health and disease.