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

Autor: Wilson MM; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Callens C; Institut de Génétique et Développement de Rennes, Centre National de la Recherche Scientifique, Rennes, France., Le Gallo M; INSERM U1242, Rennes 1 University, Rennes, France.; Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France., Mironov S; Institut de Génétique et Développement de Rennes, Centre National de la Recherche Scientifique, Rennes, France., Ding Q; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA., Salamagnon A; Institut de Génétique et Développement de Rennes, Centre National de la Recherche Scientifique, Rennes, France., Chavarria TE; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Viel R; Plateforme d'Histopathologie de Haute Précision (H2P2), Rennes, France., Peasah AD; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Bhutkar A; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA., Martin S; INSERM U1242, Rennes 1 University, Rennes, France.; Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France., Godey F; INSERM U1242, Rennes 1 University, Rennes, France.; Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France., Tas P; INSERM U1242, Rennes 1 University, Rennes, France.; Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France., Kang HS; Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA., Juin PP; CRCINA, INSERM, Université de Nantes, Nantes, France., Jetten AM; Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA., Visvader JE; Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia., Weinberg RA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.; MIT Department of Biology and the Whitehead Institute, Cambridge, MA, USA., Attanasio M; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA., Prigent C; Institut de Génétique et Développement de Rennes, Centre National de la Recherche Scientifique, Rennes, France.; CRBM, CNRS, Université de Montpellier, Montpellier, France., Lees JA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Guen VJ; Institut de Génétique et Développement de Rennes, Centre National de la Recherche Scientifique, Rennes, France.; CRCINA, INSERM, Université de Nantes, Nantes, France.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2021 Oct 29; Vol. 7 (44), pp. eabf6063. Date of Electronic Publication: 2021 Oct 27.
DOI: 10.1126/sciadv.abf6063
Abstrakt: 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.
Databáze: MEDLINE