GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.

The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications of mitochondria transfer on tumor biology are poorly understood. Here we show that mitochondria transfer is a prevalent phenomenon in glioblastoma (GBM), the most frequent and malignant primary brain tumor. We identified horizontal mitochondria transfer from astrocytes as a mechanism that enhances tumorigenesis in GBM. This transfer is dependent on network-forming intercellular connections between GBM cells and astrocytes, which are facilitated by growth-associated protein 43 (GAP43), a protein involved in neuron axon regeneration and astrocyte reactivity. The acquisition of astrocyte mitochondria drives an increase in mitochondrial respiration and upregulation of metabolic pathways linked to proliferation and tumorigenicity. Functionally, uptake of astrocyte mitochondria promotes cell cycle progression to proliferative G2/M phases and enhances self-renewal and tumorigenicity of GBM. Collectively, our findings reveal a host-tumor interaction that drives proliferation and self-renewal of cancer cells, providing opportunities for therapeutic development. © 2023. The Author(s).

Citation

Dionysios C Watson, Defne Bayik, Simon Storevik, Shannon Sherwin Moreino, Samuel A Sprowls, Jianhua Han, Mina Thue Augustsson, Adam Lauko, Palavalasa Sravya, Gro Vatne Røsland, Katie Troike, Karl Johan Tronstad, Sabrina Wang, Katharina Sarnow, Kristen Kay, Taral R Lunavat, Daniel J Silver, Sahil Dayal, Justin Vareecal Joseph, Erin Mulkearns-Hubert, Lars Andreas Rømo Ystaas, Gauravi Deshpande, Joris Guyon, Yadi Zhou, Capucine R Magaut, Juliana Seder, Laura Neises, Sarah E Williford, Johannes Meiser, Andrew J Scott, Peter Sajjakulnukit, Jason A Mears, Rolf Bjerkvig, Abhishek Chakraborty, Thomas Daubon, Feixiong Cheng, Costas A Lyssiotis, Daniel R Wahl, Anita B Hjelmeland, Jubayer A Hossain, Hrvoje Miletic, Justin D Lathia. GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity. Nature cancer. 2023 May;4(5):648-664

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PMID: 37169842

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