TY - JOUR
T1 - GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity
AU - Watson, Dionysios C.
AU - Bayik, Defne
AU - Storevik, Simon
AU - Moreino, Shannon Sherwin
AU - Sprowls, Samuel A.
AU - Han, Jianhua
AU - Augustsson, Mina Thue
AU - Lauko, Adam
AU - Sravya, Palavalasa
AU - Røsland, Gro Vatne
AU - Troike, Katie
AU - Tronstad, Karl Johan
AU - Wang, Sabrina
AU - Sarnow, Katharina
AU - Kay, Kristen
AU - Lunavat, Taral R.
AU - Silver, Daniel J.
AU - Dayal, Sahil
AU - Joseph, Justin Vareecal
AU - Mulkearns-Hubert, Erin
AU - Ystaas, Lars Andreas Rømo
AU - Deshpande, Gauravi
AU - Guyon, Joris
AU - Zhou, Yadi
AU - Magaut, Capucine R.
AU - Seder, Juliana
AU - Neises, Laura
AU - Williford, Sarah E.
AU - Meiser, Johannes
AU - Scott, Andrew J.
AU - Sajjakulnukit, Peter
AU - Mears, Jason A.
AU - Bjerkvig, Rolf
AU - Chakraborty, Abhishek
AU - Daubon, Thomas
AU - Cheng, Feixiong
AU - Lyssiotis, Costas A.
AU - Wahl, Daniel R.
AU - Hjelmeland, Anita B.
AU - Hossain, Jubayer A.
AU - Miletic, Hrvoje
AU - Lathia, Justin D.
N1 - Funding Information:
We thank A. Mendelsohn for illustrations; the LRI Flow Cytometry Core (an ISAC-recognized Shared Resource Laboratory), the LRI Imaging Core, J. Peterson, A. Mulya, S. Prasad, B. Nordanger and H. S. Saed for their technical assistance and discussions; the Molecular Imaging Center and the Flow Cytometry Core Facility in Bergen, Norway, for technical support; F. Kruyt for the GG16 cell line (University of Groningen, Netherlands) and A. Andren and L. Zhang for technical support with metabolomics analysis. This work used flow cytometry and sorting equipment supported with funds from the Clinical and Translational Science Collaborative of Cleveland, UL1TR002548, from the National Center for Advancing Translational Sciences. This work used the Leica SP8 confocal microscope that was purchased with funding from National Institutes of Health SIG grant 1S10OD019972-01. Funding for this study was provided by Lerner Research Institute, Cleveland Clinic (J.D.L.), Case Comprehensive Cancer Center (J.D.L.), National Institutes of Health grant R35 NS127083 (J.D.L.), VeloSano Cancer Research Pilot Award (D.C.W., D.B. and J.D.L.), 2020 VeloSano Trainee Dream Experiment (D.C.W.), National Institutes of Health grants 5T32AI007024 and 5TL1TR002549 (D.C.W.), National Institutes of Health grant K99CA248611 (D.B.), Helse Vest fellowship grant (S.S.), University of Bergen fellowship grant (S.S.M.), The Research Council of Norway grant 325883 (S.S.M. and H.M.), Norwegian Cancer Society grant 197933 (J.H. and H.M.), National Institutes of Health grant K00CA253768 (S.A.S.), National Institutes of Health grant F30CA250254 (A.L.), National Institutes of Health grant F31CA264849 (K.K.) and National Institutes of Health grant F32CA260735 (A.J.S.).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85159126766&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37169842
U2 - 10.1038/s43018-023-00556-5
DO - 10.1038/s43018-023-00556-5
M3 - Article
C2 - 37169842
SN - 2662-1347
VL - 4
SP - 648
EP - 664
JO - Nature Cancer
JF - Nature Cancer
IS - 5
ER -