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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)444-459.e7
JournalCancer Cell
Volume32
Issue number4
DOIs
Publication statusPublished - Oct 9 2017

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Keywords

  • breast cancer
  • Class II PI3K
  • clathrin
  • genomic stability
  • inter-microtubule bridge complex
  • mitosis
  • paclitaxel
  • spindle assembly checkpoint
  • TACC3

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Gulluni, F., Martini, M., De Santis, M. C., Campa, C. C., Ghigo, A., Margaria, J. P., Ciraolo, E., Franco, I., Ala, U., Annaratone, L., Disalvatore, D., Bertalot, G., Viale, G., Noatynska, A., Compagno, M., Sigismund, S., Montemurro, F., Thelen, M., Fan, F., ... Hirsch, E. (2017). Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function. Cancer Cell, 32(4), 444-459.e7. https://doi.org/10.1016/j.ccell.2017.09.002