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TCTP regulates genotoxic stress and tumorigenicity via intercellular vesicular signaling

Amson, Robert ; Senff-Ribeiro, Andrea ; Karafin, Teele ; Lespagnol, Alexandra ; Honoré, Joane ; Baylot, Virginie ; Banroques, Josette ; Tanner, N Kyle ; Chamond, Nathalie ; Dimitrov, Jordan D ; Hoebeke, Johan ; Droin, Nathalie M ; Job, Bastien ; Piard, Jonathan ; Bommer, Ulrich-Axel ; Choi, Kwang-Wook ; Abdelfatah, Sara ; Efferth, Thomas ; Telerman, Stephanie B ; Geyer, Felipe Correa ; Reis-Filho, Jorge ; Telerman, Adam

Springer Science and Business Media LLC 2024-04

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  • Title:
    TCTP regulates genotoxic stress and tumorigenicity via intercellular vesicular signaling
  • Author: Amson, Robert ; Senff-Ribeiro, Andrea ; Karafin, Teele ; Lespagnol, Alexandra ; Honoré, Joane ; Baylot, Virginie ; Banroques, Josette ; Tanner, N Kyle ; Chamond, Nathalie ; Dimitrov, Jordan D ; Hoebeke, Johan ; Droin, Nathalie M ; Job, Bastien ; Piard, Jonathan ; Bommer, Ulrich-Axel ; Choi, Kwang-Wook ; Abdelfatah, Sara ; Efferth, Thomas ; Telerman, Stephanie B ; Geyer, Felipe Correa ; Reis-Filho, Jorge ; Telerman, Adam
  • Subjects: Animals ; Apoptosis ; Biomarkers, Tumor ; Bystander Effect ; Humans ; Mice ; Neoplasms ; Signal Transduction ; Signaling ; Small Extracellular Vesicles (sEVs) ; Tumor Reprogramming ; Tumor Reversion
  • Description: Acknowledgements: AT and RA dedicate this work to Susan M. MacDonald in recognition for her superb work, sharing always the experimental data, for her constant support and help. We thank Christelle Martin, Karelia Lipson, Catherine Cailleau, Aude Queixalos, René Papion-Duchateau at the animal facility, SEAT/CNRS, for their help in generating the Tctp-inducible knockout mice. Alexandre Diet, Marie-Laure Dessain and Emilie Bouvier at TAAM-Phenomin and Ayma Galland at the animal facility of Université Paris-Saclay for taking care of the mice colonies. We thank Christopher M. Johnson (LMB, University of Cambridge) for advice and help with the ITC analysis and Cyril Catelain and Philippe Rameau for their expertise in FACS analysis. This work was supported by grants from INCa Projets libres 2013-1-PL BIO-10-IGR-1 « Biologie et Sciences du Cancer » 2013, the French National Agency for Research (ANR, ANR-09-BLAN-0292) and LabEx LERMIT to A.T., and Odyssea fund to RA. ASR was supported by a fellowship from Science without Borders (CNPq), CAPES-COFECUB and Federal University of Parana (UFPR, Brazil). TK was supported by a doctoral fellowship from MESR, Ecole Doctorale de Cancérologie Paris XI. The synopsis image has been created with BioRender.com. Funder: LabEx Lermit Funder: Odyssea fund Funder: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); doi: http://dx.doi.org/10.13039/501100002322 Funder: Science without Borders (CNPq) Funder: Federal University of Parana (UFPR, Brazil) Funder: Fellowship from MESR, Ecole Doctorale de Cancérologie Paris XI Oncogenic intercellular signaling is regulated by extracellular vesicles (EVs), but the underlying mechanisms remain mostly unclear. Since TCTP (translationally controlled tumor protein) is an EV component, we investigated whether it has a role in genotoxic stress signaling and malignant transformation. By generating a Tctp-inducible knockout mouse model (Tctp-/f-), we report that Tctp is required for genotoxic stress-induced apoptosis signaling via small EVs (sEVs). Human breast cancer cells knocked-down for TCTP show impaired spontaneous EV secretion, thereby reducing sEV-dependent malignant growth. Since Trp53-/- mice are prone to tumor formation, we derived tumor cells from Trp53-/-;Tctp-/f- double mutant mice and describe a drastic decrease in tumori-genicity with concomitant decrease in sEV secretion and content. Remarkably, Trp53-/-;Tctp-/f- mice show highly prolonged survival. Treatment of Trp53-/- mice with sertraline, which inhibits TCTP function, increases their survival. Mechanistically, TCTP binds DDX3, recruiting RNAs, including miRNAs, to sEVs. Our findings establish TCTP as an essential protagonist in the regulation of sEV-signaling in the context of apoptosis and tumorigenicity.
  • Publisher: Springer Science and Business Media LLC
  • Creation Date: 2024-04
  • Language: English
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