title: A neuronal network of mitochondrial dynamics regulates metastasis.
abstract: The role of mitochondria in cancer is controversial. Using a genome-wide shRNA screen, we now show that tumours reprogram a network of mitochondrial dynamics operative in neurons, including syntaphilin (SNPH), kinesin KIF5B and GTPase Miro1/2 to localize mitochondria to the cortical cytoskeleton and power the membrane machinery of cell movements. When expressed in tumours, SNPH inhibits the speed and distance travelled by individual mitochondria, suppresses organelle dynamics, and blocks chemotaxis and metastasis, in vivo. Tumour progression in humans is associated with downregulation or loss of SNPH, which correlates with shortened patient survival, increased mitochondrial trafficking to the cortical cytoskeleton, greater membrane dynamics and heightened cell invasion. Therefore, a SNPH network regulates metastatic competence and may provide a therapeutic target in cancer.
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.|Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Caino
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.|Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Department of Electrical and Computer Engineering, Drexel University College of Engineering, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Angeline
authors.initials: A
authors.lastname: Aguinaldo
authors.affiliation: Department of Electrical and Computer Engineering, Drexel University College of Engineering, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Wait
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.|Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Bryant
authors.affiliation: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.affiliation: Imaging Shared Resource, The Wistar Institute Cancer Center, Philadelphia, Pennsylvania 19104, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Hayden
authors.affiliation: Istituto Nazionale Genetica Molecolare 'Romeo and Enrica Invernizzi', Milan 20122, Italy.|Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.|Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
authors.forename: Valentina
authors.identifier: 0000-0003-4416-6216
authors.initials: V
authors.lastname: Vaira
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.|Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
authors.forename: Annamaria
authors.identifier: 0000-0002-4247-4365
authors.initials: A
authors.lastname: Morotti
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.|Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan 20122, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrero
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.|Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
authors.forename: Silvano
authors.identifier: 0000-0002-9744-6951
authors.initials: S
authors.lastname: Bosari
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.|Translational Tumor Immunology Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Gabrilovich
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.|Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
authors.affiliation: Department of Electrical and Computer Engineering, Drexel University College of Engineering, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Cohen
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.|Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
mesh_terms: D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D053858:Metabolic Networks and Pathways / Q000502:physiology; D063154:Mitochondrial Dynamics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C488101:KIF5B protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; C405513:SNPH protein, human; D033921:Vesicular Transport Proteins; C473124:RHOT1 protein, human; C473125:RHOT2 protein, human; D016547:Kinesins; D020741:rho GTP-Binding Proteins