Journal
CANCER CELL
Volume 32, Issue 4, Pages 444-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2017.09.002
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Funding
- Associazione Italiana Ricerca Cancro (AIRC) [161813]
- Compagnia di San Paolo
- World Wide Cancer Research Association [151324]
- Fondazione Umberto Veronesi fellowship
- Fondazione Italiana Ricerca Cancro (FIRC) fellowships
- AIRC [MFAG13310, IG 11904, MCO 10.000, IG-12023, MFAG 10708, IG 14404]
- Helmut Horten Foundation
- SNF-project [31003A_160006]
- University of Geneva
- Louis-Jeantet Foundation
- MIUR (the Italian Ministry of University and Scientific Research)
- Italian Ministry of Health
- NIH [R01 CA196703-01]
- Worldwide Cancer Research [12-0216]
- European Research Council (Mammastem Project)
- Monzino Foundation
- Swiss National Science Foundation (SNF) [31003A_160006] Funding Source: Swiss National Science Foundation (SNF)
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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 alpha (PI3K-C2 alpha) acting as limiting scaffold protein organizing clathrin and TACC3 complex crosslinking K-fibers. Downregulation of PI3K-C2 alpha causes spindle alterations, delayed anaphase onset, and aneuploidy, indicating that PI3K-C2 alpha expression is required for genomic stability. Reduced abundance of PI3K-C2 alpha 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-C2 alpha increases sensitivity to taxane-based therapy in pre-clinical models and in neoadjuvant settings.
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