PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion

M. Cecilia Caino, Jagadish C. Ghosh, Young Chan Chae, Valentina Vaira, Dayana B. Rivadeneira, Alice Faversani, Paolo Rampini, Andrew V. Kossenkov, Katherine M. Aird, Rugang Zhang, Marie R. Webster, Ashani T. Weeraratna, Silvano Bosari, Lucia R. Languino, Dario C. Altieri

Research output: Contribution to journalArticlepeer-review

105 Scopus citations


Molecular therapies are hallmarks of "personalized" medicine, but how tumors adapt to these agents is not well-understood. Here we show that small-molecule inhibitors of phosphatidylinositol 3-kinase (PI3K) currently in the clinic induce global transcriptional reprogramming in tumors, with activation of growth factor receptors, (re)phosphorylation of Akt and mammalian target of rapamycin (mTOR), and increased tumor cell motility and invasion. This response involves redistribution of energetically active mitochondria to the cortical cytoskeleton, where they support membrane dynamics, turnover of focal adhesion complexes, and random cell motility. Blocking oxidative phosphorylation prevents adaptive mitochondrial trafficking, impairs membrane dynamics, and suppresses tumor cell invasion. Therefore, "spatiotemporal" mitochondrial respiration adaptively induced by PI3K therapy fuels tumor cell invasion, and may provide an important antimetastatic target.

Original languageEnglish (US)
Pages (from-to)8638-8643
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number28
StatePublished - Jul 14 2015
Externally publishedYes


  • Cell invasion
  • Cytoskeleton
  • Mitochondria
  • Molecular therapy
  • PI3K

ASJC Scopus subject areas

  • General


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