| Title: |
Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability |
| Authors: |
Ghosh, Jagadish C; Perego, Michela; Agarwal, Ekta; Bertolini, Irene; Wang, Yuan; Goldman, Aaron R; Tang, Hsin-Yao; Kossenkov, Andrew V; Libby, Catherine J; Languino, Lucia R; Plow, Edward F; Morotti, Annamaria; Ottobrini, Luisa; Locatelli, Marco; Speicher, David W; Caino, M Cecilia; Cassel, Joel; Salvino, Joseph M; Robert, Marie E; Vaira, Valentina; Altieri, Dario C |
| Source: |
Department of Cancer Biology Faculty Papers |
| Publisher Information: |
Jefferson Digital Commons |
| Publication Year: |
2022 |
| Collection: |
Jefferson Digital Commons (Thomas Jefferson University, Philadelphia) |
| Subject Terms: |
cell motility; metastasis; mitochondria; Medicine and Health Sciences; Oncology |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://jdc.jefferson.edu/cbfp/188; https://jdc.jefferson.edu/context/cbfp/article/1195/viewcontent/pnas.2115624119.pdf |
| Availability: |
https://jdc.jefferson.edu/cbfp/188; https://jdc.jefferson.edu/context/cbfp/article/1195/viewcontent/pnas.2115624119.pdf |
| Rights: |
http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.FE46D4DE |
| Database: |
BASE |