Hormone-responsive progenitors have a unique identity and exhibit high motility during mammary morphogenesis
Caleb A. Dawson,
Michael J.G. Milevskiy,
Bianca D. Capaldo,
Raymond K.H. Yip,
Xiaoyu Song,
François Vaillant,
Lexie Prokopuk,
Felicity C. Jackling,
Gordon K. Smyth,
Yunshun Chen,
Geoffrey J. Lindeman,
Jane E. Visvader
Affiliations
Caleb A. Dawson
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
Michael J.G. Milevskiy
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
Bianca D. Capaldo
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
Raymond K.H. Yip
Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Xiaoyu Song
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
François Vaillant
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
Lexie Prokopuk
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
Felicity C. Jackling
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Gordon K. Smyth
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC 3010, Australia
Yunshun Chen
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Geoffrey J. Lindeman
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3010, Australia; Parkville Familial Cancer Centre and Department of Medical Oncology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC 3052, Australia
Jane E. Visvader
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Corresponding author
Summary: Hormone-receptor-positive (HR+) luminal cells largely mediate the response to estrogen and progesterone during mammary gland morphogenesis. However, there remains a lack of consensus on the precise nature of the precursor cells that maintain this essential HR+ lineage. Here we refine the identification of HR+ progenitors and demonstrate their unique regenerative capacity compared to mature HR+ cells. HR+ progenitors proliferate but do not expand, suggesting rapid differentiation. Subcellular resolution, 3D intravital microscopy was performed on terminal end buds (TEBs) during puberty to dissect the contribution of each luminal lineage. Surprisingly, HR+ TEB progenitors were highly elongated and motile compared to columnar HR– progenitors and static, conoid HR+ cells within ducts. This dynamic behavior was also observed in response to hormones. Development of an AI model for motility dynamics analysis highlighted stark behavioral changes in HR+ progenitors as they transitioned to mature cells. This work provides valuable insights into how progenitor behavior contributes to mammary morphogenesis.
