Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function

Gulluni, Federico; Martini, Miriam; De Santis, Maria Chiara; Campa, Carlo Cosimo; Ghigo, Alessandra; Margaria, Jean Piero; Ciraolo, Elisa; Franco, Irene; Ala, Ugo; Annaratone, Laura; Disalvatore, Davide; Bertalot, Giovanni; Viale, Giuseppe; Noatynska, Anna; Compagno, Mara; Sigismund, Sara; Montemurro, Filippo; Thelen, Marcus; Fan, Fan; Meraldi, Patrick; Marchiò, Caterina; Pece, Salvatore; Sapino, Anna; Chiarle, Roberto; Di Fiore, Pier Paolo; Hirsch, Emilio

doi:10.1016/j.ccell.2017.09.002

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Title		Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function
Authors		Gulluni, Federico Martini, Miriam De Santis, Maria Chiara Campa, Carlo Cosimo Ghigo, Alessandra Margaria, Jean Piero Ciraolo, Elisa Franco, Irene Ala, Ugo Annaratone, Laura Disalvatore, Davide Bertalot, Giovanni Viale, Giuseppe Noatynska, Anna Compagno, Mara Sigismund, Sara Montemurro, Filippo Thelen, Marcus Fan, Fan Meraldi, Patrick Marchiò, Caterina Pece, Salvatore Sapino, Anna Chiarle, Roberto Di Fiore, Pier Paolo Hirsch, Emilio show all authors [1 - 26]
Published in		Cancer Cell. 2017, vol. 32, no. 4, p. 444-459.e7
Abstract		Proper organization of the mitotic spindle is key to genetic stability, but molecular components of inter-microtubule bridges that crosslink kinetochore fibers (K-fibers) are still largely unknown. Here we identify a kinase-independent function of class II phosphoinositide 3-OH kinase α (PI3K-C2α) acting as limiting scaffold protein organizing clathrin and TACC3 complex crosslinking K-fibers. Downregulation of PI3K-C2α causes spindle alterations, delayed anaphase onset, and aneuploidy, indicating that PI3K-C2α expression is required for genomic stability. Reduced abundance of PI3K-C2α in breast cancer models initially impairs tumor growth but later leads to the convergent evolution of fast-growing clones with mitotic checkpoint defects. As a consequence of altered spindle, loss of PI3K-C2α increases sensitivity to taxane-based therapy in pre-clinical models and in neoadjuvant settings.
Keywords		Animals — Breast Neoplasms/drug therapy/genetics/pathology — Cell Cycle Proteins/physiology — Cell Proliferation — Genomic Instability — Humans — MCF-7 Cells — Mad2 Proteins/physiology — Mice — Microtubule-Associated Proteins/physiology — Nuclear Proteins/physiology — Phosphatidylinositol 3-Kinases/physiology — Spindle Apparatus/physiology — Taxoids/therapeutic use
Identifiers		DOI: 10.1016/j.ccell.2017.09.002 PMID: 29017056
Full text		Article (Published version) (2.4 MB) - Limited access to UNIGE
Structures		Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme
Research group		Groupe Meraldi Patrick (physiologie cellulaire et métabolisme) (922)
Citation (ISO format)		GULLUNI, Federico et al. Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function. In: Cancer Cell, 2017, vol. 32, n° 4, p. 444-459.e7. doi: 10.1016/j.ccell.2017.09.002 https://archive-ouverte.unige.ch/unige:107106