An EMT-primary cilium-GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis

Molly M Wilson (1) , Céline Callens (2) , Matthieu Le Gallo (3) , Svetlana Mironov (2) , Qiong Ding (4) , Amandine Salamagnon (2) , Tony E Chavarria (1) , Roselyne Viel (5) , Abena D Peasah (1) , Arjun Bhutkar (1) , Sophie Martin (3, 6) , Florence Godey (3, 6) , Patrick Tas (3, 6) , Hong Soon Kang (7) , Philippe Juin (8) , Anton M Jetten (7) , Jane E Visvader (9) , Robert A Weinberg (1) , Massimo Attanasio (4) , Claude Prigent (2, 10) , Jacqueline A Lees (1) , Vincent J Guen (2, 8)

1 MIT - Massachusetts Institute of Technology
2 IGDR - Institut de Génétique et Développement de Rennes
3 COSS - Chemistry, Oncogenesis, Stress and Signaling
4 Carver College of Medicine, University of Iowa
5 H2P2 - H2P2 - Histo Pathologie Hight Precision
6 CRLCC - CRLCC Eugène Marquis
7 NIEHS-NIH - National Institute of Environmental Health Sciences [Durham, NC, USA]
8 CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
9 University of Melbourne
10 CRBM - Centre de recherche en Biologie cellulaire de Montpellier

The epithelial-mesenchymal transition (EMT) and primary ciliogenesis induce stem cell properties in basal mammary stem cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis upon entry into intermediate EMT states by activating ciliogenesis inducers, including FGFR1. The resulting primary cilia promote ubiquitination and inactivation of a transcriptional repressor, GLIS2, which localizes to the ciliary base. We show that GLIS2 inactivation promotes MaSC stemness, and GLIS2 is required for normal mammary gland development. Moreover, GLIS2 inactivation is required to induce the proliferative and tumorigenic capacities of the mammary tumor–initiating cells (MaTICs) of claudin-low breast cancers. Claudin-low breast tumors can be segregated from other breast tumor subtypes based on a GLIS2-dependent gene expression signature. Collectively, our findings establish molecular mechanisms by which EMT programs induce ciliogenesis to control MaSC and MaTIC stemness, mammary gland development, and claudin-low breast cancer formation.

Domaines: Cancer; Génétique

Molly M Wilson, Céline Callens, Matthieu Le Gallo, Svetlana Mironov, Qiong Ding, et al.. An EMT-primary cilium-GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis. Science Advances , 2021, 7 (44), pp.eabf6063. ⟨10.1126/sciadv.abf6063⟩. ⟨hal-03420207⟩