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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.
Affiliation
  • Gulluni F; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy.
  • Martini M; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy. Electronic address: miriam.martini@unito.it.
  • De Santis MC; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy.
  • Campa CC; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy.
  • Ghigo A; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy.
  • Margaria JP; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy.
  • Ciraolo E; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy.
  • Franco I; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy.
  • Ala U; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy.
  • Annaratone L; Department of Medical Sciences, University of Torino, Turin, Italy; Pathology Unit, Department of Laboratory Medicine, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
  • Disalvatore D; IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.
  • Bertalot G; Program of Molecular Medicine, IEO, European Institute of Oncology, Milan, Italy.
  • Viale G; Division of Pathology, European Institute of Oncology, Milan, Italy; Department of Oncology and Hemato-oncology (DIPO), University of Milan, Milan, Italy.
  • Noatynska A; Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
  • Compagno M; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
  • Sigismund S; IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.
  • Montemurro F; Unit of Investigative Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo (TO), Italy.
  • Thelen M; Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
  • Fan F; Department of Biological Science and Bioengineering, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China.
  • Meraldi P; Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
  • Marchiò C; Department of Medical Sciences, University of Torino, Turin, Italy; Pathology Unit, Department of Laboratory Medicine, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
  • Pece S; Program of Molecular Medicine, IEO, European Institute of Oncology, Milan, Italy; Department of Oncology and Hemato-oncology (DIPO), University of Milan, Milan, Italy.
  • Sapino A; Department of Medical Sciences, University of Torino, Turin, Italy; Unit of Pathology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo (TO), Italy.
  • Chiarle R; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
  • Di Fiore PP; IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy; Program of Molecular Medicine, IEO, European Institute of Oncology, Milan, Italy; Department of Oncology and Hemato-oncology (DIPO), University of Milan, Milan, Italy.
  • Hirsch E; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy. Electronic address: emilio.hirsch@unito.it.
Cancer Cell ; 32(4): 444-459.e7, 2017 10 09.
Article in En | MEDLINE | ID: mdl-29017056
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Breast Neoplasms / Phosphatidylinositol 3-Kinases / Genomic Instability / Spindle Apparatus Limits: Animals / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2017 Type: Article Affiliation country: Italy
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Breast Neoplasms / Phosphatidylinositol 3-Kinases / Genomic Instability / Spindle Apparatus Limits: Animals / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2017 Type: Article Affiliation country: Italy