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 journalArticle

77 Citations (Scopus)

Abstract

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
Volume112
Issue number28
DOIs
StatePublished - Jul 14 2015

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Phosphatidylinositol 3-Kinase
Neoplasms
Cell Movement
Therapeutics
Precision Medicine
Focal Adhesions
Membranes
Growth Factor Receptors
Oxidative Phosphorylation
Sirolimus
Cytoskeleton
Mitochondria
Respiration
Phosphorylation

All Science Journal Classification (ASJC) codes

  • General

Cite this

Caino, M. C., Ghosh, J. C., Chae, Y. C., Vaira, V., Rivadeneira, D. B., Faversani, A., ... Altieri, D. C. (2015). PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion. Proceedings of the National Academy of Sciences of the United States of America, 112(28), 8638-8643. https://doi.org/10.1073/pnas.1500722112
Caino, M. Cecilia ; Ghosh, Jagadish C. ; Chae, Young Chan ; Vaira, Valentina ; Rivadeneira, Dayana B. ; Faversani, Alice ; Rampini, Paolo ; Kossenkov, Andrew V. ; Aird, Katherine M. ; Zhang, Rugang ; Webster, Marie R. ; Weeraratna, Ashani T. ; Bosari, Silvano ; Languino, Lucia R. ; Altieri, Dario C. / PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 28. pp. 8638-8643.
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Caino, MC, Ghosh, JC, Chae, YC, Vaira, V, Rivadeneira, DB, Faversani, A, Rampini, P, Kossenkov, AV, Aird, KM, Zhang, R, Webster, MR, Weeraratna, AT, Bosari, S, Languino, LR & Altieri, DC 2015, 'PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 28, pp. 8638-8643. https://doi.org/10.1073/pnas.1500722112

PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion. / Caino, M. Cecilia; Ghosh, Jagadish C.; Chae, Young Chan; Vaira, Valentina; Rivadeneira, Dayana B.; Faversani, Alice; Rampini, Paolo; Kossenkov, Andrew V.; Aird, Katherine M.; Zhang, Rugang; Webster, Marie R.; Weeraratna, Ashani T.; Bosari, Silvano; Languino, Lucia R.; Altieri, Dario C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 28, 14.07.2015, p. 8638-8643.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion

AU - Caino, M. Cecilia

AU - Ghosh, Jagadish C.

AU - Chae, Young Chan

AU - Vaira, Valentina

AU - Rivadeneira, Dayana B.

AU - Faversani, Alice

AU - Rampini, Paolo

AU - Kossenkov, Andrew V.

AU - Aird, Katherine M.

AU - Zhang, Rugang

AU - Webster, Marie R.

AU - Weeraratna, Ashani T.

AU - Bosari, Silvano

AU - Languino, Lucia R.

AU - Altieri, Dario C.

PY - 2015/7/14

Y1 - 2015/7/14

N2 - 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.

AB - 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.

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JO - Proceedings of the National Academy of Sciences of the United States of America

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