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. Gulluni et al. reveal a kinase-independent scaffolding function of PI3K-C2α that affects mitotic spindle formation. Reduced levels of PI3K-C2α reduce tumor growth initially but provide a growth advantage later in mouse models of breast cancer. Loss of PI3K-C2α also increases sensitivity of tumors to taxanes.

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

GULLUNI, FEDERICO;MARTINI, MIriam
Co-first
;
DE SANTIS, MARIA CHIARA;CAMPA, CARLO COSIMO;GHIGO, Alessandra;MARGARIA, JEAN PIERO;CIRAOLO, Elisa;FRANCO, IRENE;ALA, UGO;ANNARATONE, LAURA;VIALE, GIUSEPPE;COMPAGNO, MARA;MARCHIO', Caterina;SAPINO, Anna;CHIARLE, Roberto;HIRSCH, Emilio
Last
2017

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. Gulluni et al. reveal a kinase-independent scaffolding function of PI3K-C2α that affects mitotic spindle formation. Reduced levels of PI3K-C2α reduce tumor growth initially but provide a growth advantage later in mouse models of breast cancer. Loss of PI3K-C2α also increases sensitivity of tumors to taxanes.
32
4
444
459.e7
https://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30406-3
Class II PI3K; TACC3; breast cancer; clathrin; genomic stability; inter-microtubule bridge complex; mitosis; paclitaxel; spindle assembly checkpoint
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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1650061
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