Poster Presentation 40th Annual Lorne Genome Conference 2019

Mammary stem cell hierarchy maintenance by GPSM2 and asymmetric cell division (#222)

Michal Milgrom Hoffman 1 , Nathan Godde 2 , Kara Britt 3 , Tanja Kinwel 1 , Fumio Matsuzaki 4 , Patrick Humbert 1
  1. La Trobe Institute for Molecular Science, Bundoora, VIC
  2. CSIRO, Geelong, VIC
  3. Peter MacCallum Cancer Centre, Melbourne, VIC
  4. RIKEN Center for Developmental Biology, Kobe, Japan

One of the main characteristics of epithelial structures such as the mammary gland is the active maintenance of tissue polarity, or coordinated cellular asymmetry, during developmental processes. Perturbation of polarity regulatory mechanisms has been linked to malignant progression and is indeed one of the earliest events in epithelial tumorigenesis. During Asymmetric Cell Division (ACD) which dictates the balance between renewal of progenitor cells and differentiation, GPSM2 (also known as LGN/Pins/raps) mediates polarity cues to direct spindle orientation. Although substantial work has elucidated GPSM2 function and interaction with signaling pathways on a cellular level, the relevance of these findings in mammary gland biology is largely unknown. Here, we report a crucial role for GPSM2 in maintaining mammary architecture and progenitor cell fate. GPSM2 loss of function in the mouse model resulted in disoriented spindle formation, an increase of epithelial invasion during puberty, mammary ductal ectasia in mature mice and inhibition of lobuloalveolar differentiation during pregnancy. These phenotypical changes are due to sensitivity of mammary stem cells (MaSC) to GPSM2 deregulation, which lead to reduction in population size and clonal potential. The remaining MaSC population, although contributing to a functional mammary tissue, accumulated gene expression changes involved in chemotaxis, cell adhesion and immune response.  Altogether our studies describe a distinct role for GPSM2 in the control of MaSC turnover and subsequent mammary development. We propose that deregulation of GPSM can trigger a response in MaSC that predisposes to malignancy.