2. Academic Validation
  3. Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability

Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability

  • Proc Natl Acad Sci U S A. 2022 Feb 22;119(8):e2115624119. doi: 10.1073/pnas.2115624119.
Jagadish C Ghosh 1 2,  Michela Perego 1 2,  Ekta Agarwal 1 2,  Irene Bertolini 1 2,  Yuan Wang 1 2,  Aaron R Goldman 3,  Hsin-Yao Tang 3,  Andrew V Kossenkov 4 5,  Catherine J Landis 1 2,  Lucia R Languino 1 6,  Edward F Plow 1 7,  Annamaria Morotti 8 9,  Luisa Ottobrini 9,  Marco Locatelli 9 10,  David W Speicher 1 5,  M Cecilia Caino 11,  Joel Cassel 12,  Joseph M Salvino 12 13,  Marie E Robert 14,  Valentina Vaira 8 9,  Dario C Altieri 15 2
Affiliations

Affiliations

  • 1 Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104.
  • 2 Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104.
  • 3 Proteomics and Metabolomics Shared Resource, The Wistar Institute, Philadelphia, PA 19104.
  • 4 Bioinformatics Shared Resource, The Wistar Institute, Philadelphia, PA 19104.
  • 5 Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104.
  • 6 Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
  • 7 Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
  • 8 Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
  • 9 Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
  • 10 Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
  • 11 Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045.
  • 12 Molecular Screening and Protein Expression Shared Resource, The Wistar Institute, Philadelphia, PA 19104.
  • 13 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104.
  • 14 Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
  • 15 Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104; daltieri@wistar.org.
PMID: 35177476 DOI: 10.1073/pnas.2115624119
Abstract

Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Here, we show that many human tumors have heterogeneous and often reduced levels of Mic60, or Mitofilin, an essential scaffold of mitochondrial structure. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic60 depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling. In turn, this induces epithelial-mesenchymal transition (EMT), activates tumor cell movements through exaggerated mitochondrial dynamics, and promotes metastatic dissemination in vivo. In a small-molecule drug screen, compensatory activation of stress response (GCN2) and survival (Akt) signaling maintains the viability of Mic60-low tumors and provides a selective therapeutic vulnerability. These data demonstrate that acutely damaged, "ghost" mitochondria drive tumor progression and expose an actionable therapeutic target in metastasis-prone cancers.

Keywords

cell motility; metastasis; mitochondria.

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