Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors
Abstract We find that NUPR1, a stress-associated intrinsically disordered protein, induced droplet formation via liquid–liquid phase separation (LLPS). NUPR1-driven LLPS was crucial for the creation of NUPR1-dependent stress granules (SGs) in pancreatic cancer cells since genetic or pharmacological...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2024-02-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-024-00032-2 |
| _version_ | 1797259107528343552 |
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| author | Patricia Santofimia-Castaño Nicolas Fraunhoffer Xi Liu Ivan Fernandez Bessone Marina Pasca di Magliano Stephane Audebert Luc Camoin Matias Estaras Manon Brenière Mauro Modesti Gwen Lomberk Raul Urrutia Philippe Soubeyran Jose Luis Neira Juan Iovanna |
| author_facet | Patricia Santofimia-Castaño Nicolas Fraunhoffer Xi Liu Ivan Fernandez Bessone Marina Pasca di Magliano Stephane Audebert Luc Camoin Matias Estaras Manon Brenière Mauro Modesti Gwen Lomberk Raul Urrutia Philippe Soubeyran Jose Luis Neira Juan Iovanna |
| author_sort | Patricia Santofimia-Castaño |
| collection | DOAJ |
| description | Abstract We find that NUPR1, a stress-associated intrinsically disordered protein, induced droplet formation via liquid–liquid phase separation (LLPS). NUPR1-driven LLPS was crucial for the creation of NUPR1-dependent stress granules (SGs) in pancreatic cancer cells since genetic or pharmacological inhibition by ZZW-115 of NUPR1 activity impeded SGs formation. The KrasG12D mutation induced oncogenic stress, NUPR1 overexpression, and promoted SGs development. Notably, enforced NUPR1 expression induced SGs formation independently of mutated KrasG12D. Mechanistically, KrasG12D expression strengthened sensitivity to NUPR1 inactivation, inducing cell death, activating caspase 3 and releasing LDH. Remarkably, ZZW-115-mediated SG-formation inhibition hampered the development of pancreatic intraepithelial neoplasia (PanINs) in Pdx1-cre;LSL-Kras G12D (KC) mice. ZZW-115-treatment of KC mice triggered caspase 3 activation, DNA fragmentation, and formation of the apoptotic bodies, leading to cell death, specifically in KrasG12D-expressing cells. We further demonstrated that, in developed PanINs, short-term ZZW-115 treatment prevented NUPR1-associated SGs presence. Lastly, a four-week ZZW-115 treatment significantly reduced the number and size of PanINs in KC mice. This study proposes that targeting NUPR1-dependent SGs formation could be a therapeutic approach to induce cell death in KrasG12D-dependent tumors. |
| first_indexed | 2024-04-24T23:04:10Z |
| format | Article |
| id | doaj.art-d6378f109e874a1da4c8222d7dc3b37c |
| institution | Directory Open Access Journal |
| issn | 1757-4684 |
| language | English |
| last_indexed | 2024-04-24T23:04:10Z |
| publishDate | 2024-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-d6378f109e874a1da4c8222d7dc3b37c2024-03-17T12:34:38ZengSpringer NatureEMBO Molecular Medicine1757-46842024-02-0116347550510.1038/s44321-024-00032-2Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumorsPatricia Santofimia-Castaño0Nicolas Fraunhoffer1Xi Liu2Ivan Fernandez Bessone3Marina Pasca di Magliano4Stephane Audebert5Luc Camoin6Matias Estaras7Manon Brenière8Mauro Modesti9Gwen Lomberk10Raul Urrutia11Philippe Soubeyran12Jose Luis Neira13Juan Iovanna14Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyDepartment of Surgery, University of MichiganCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyDivision of Research, Department of Surgery, Medical College of WisconsinGenomic Science and Precision Medicine Center (GSPMC), Medical College of WisconsinCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyIDIBE, Universidad Miguel Hernández, Edificio Torregaitán, Avda. del Ferrocarril s/nCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyAbstract We find that NUPR1, a stress-associated intrinsically disordered protein, induced droplet formation via liquid–liquid phase separation (LLPS). NUPR1-driven LLPS was crucial for the creation of NUPR1-dependent stress granules (SGs) in pancreatic cancer cells since genetic or pharmacological inhibition by ZZW-115 of NUPR1 activity impeded SGs formation. The KrasG12D mutation induced oncogenic stress, NUPR1 overexpression, and promoted SGs development. Notably, enforced NUPR1 expression induced SGs formation independently of mutated KrasG12D. Mechanistically, KrasG12D expression strengthened sensitivity to NUPR1 inactivation, inducing cell death, activating caspase 3 and releasing LDH. Remarkably, ZZW-115-mediated SG-formation inhibition hampered the development of pancreatic intraepithelial neoplasia (PanINs) in Pdx1-cre;LSL-Kras G12D (KC) mice. ZZW-115-treatment of KC mice triggered caspase 3 activation, DNA fragmentation, and formation of the apoptotic bodies, leading to cell death, specifically in KrasG12D-expressing cells. We further demonstrated that, in developed PanINs, short-term ZZW-115 treatment prevented NUPR1-associated SGs presence. Lastly, a four-week ZZW-115 treatment significantly reduced the number and size of PanINs in KC mice. This study proposes that targeting NUPR1-dependent SGs formation could be a therapeutic approach to induce cell death in KrasG12D-dependent tumors.https://doi.org/10.1038/s44321-024-00032-2KrasZZW-115Synthetic LethalityStress GranulesNUPR1 |
| spellingShingle | Patricia Santofimia-Castaño Nicolas Fraunhoffer Xi Liu Ivan Fernandez Bessone Marina Pasca di Magliano Stephane Audebert Luc Camoin Matias Estaras Manon Brenière Mauro Modesti Gwen Lomberk Raul Urrutia Philippe Soubeyran Jose Luis Neira Juan Iovanna Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors EMBO Molecular Medicine Kras ZZW-115 Synthetic Lethality Stress Granules NUPR1 |
| title | Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors |
| title_full | Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors |
| title_fullStr | Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors |
| title_full_unstemmed | Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors |
| title_short | Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors |
| title_sort | targeting nupr1 dependent stress granules formation to induce synthetic lethality in krasg12d driven tumors |
| topic | Kras ZZW-115 Synthetic Lethality Stress Granules NUPR1 |
| url | https://doi.org/10.1038/s44321-024-00032-2 |
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