title: PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion.
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.
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104;
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Caino
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104;
authors.forename: Jagadish C
authors.initials: JC
authors.lastname: Ghosh
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104;
authors.forename: Young Chan
authors.initials: YC
authors.lastname: Chae
authors.affiliation: Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi," Milan 20122, Italy; Division of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy;
authors.forename: Valentina
authors.initials: V
authors.lastname: Vaira
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104;
authors.forename: Dayana B
authors.initials: DB
authors.lastname: Rivadeneira
authors.affiliation: Division of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy;
authors.forename: Alice
authors.initials: A
authors.lastname: Faversani
authors.affiliation: Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Rampini
authors.affiliation: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104;
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104;
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Aird
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104;
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104;
authors.forename: Marie R
authors.initials: MR
authors.lastname: Webster
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104;
authors.forename: Ashani T
authors.initials: AT
authors.lastname: Weeraratna
authors.affiliation: Division of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy; Department of Pathophysiology and Organ Transplant, University of Milan, Milan 20122, Italy;
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104; Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104; daltieri@wistar.org.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
mesh_terms: D001692:Biological Transport; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000378:metabolism; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt
keywords: PI3K; cell invasion; cytoskeleton; mitochondria; molecular therapy