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

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 int...

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Bibliographic Details
Published in:Science advances 2021-10, Vol.7 (44), p.eabf6063
Main Authors: Wilson, Molly M, Callens, Céline, Le Gallo, Matthieu, Mironov, Svetlana, Ding, Qiong, Salamagnon, Amandine, Chavarria, Tony E, Viel, Roselyne, Peasah, Abena D, Bhutkar, Arjun, Martin, Sophie, Godey, Florence, Tas, Patrick, Kang, Hong Soon, Juin, Philippe P, Jetten, Anton M, Visvader, Jane E, Weinberg, Robert A, Attanasio, Massimo, Prigent, Claude, Lees, Jacqueline A, Guen, Vincent J
Format: Article
Language:English
Subjects:
Biomedicine and Life Sciences
Cancer
Cell Biology
Genetics
Life Sciences
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Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abf6063