Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors

Autores
Santofimia Castaño, Patricia; Fraunhoffer Navarro, Nicolas Alejandro; Liu, Xi; Fernández Bessone, Iván; di Magliano, Marina Pasca; Audebert, Stephane; Camoin, Luc; Estaras, Matias; Brenière, Manon; Modesti, Mauro; Lomberk, Gwen; Urrutia, Raul; Soubeyran, Philippe; Neira, Jose Luis; Iovanna, Juan
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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-KrasG12D (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.
Fil: Santofimia Castaño, Patricia. Inserm; Francia
Fil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Liu, Xi. Inserm; Francia
Fil: Fernández Bessone, Iván. Inserm; Francia
Fil: di Magliano, Marina Pasca. Michigan State University; Estados Unidos
Fil: Audebert, Stephane. Medical College Of Wisconsin; Estados Unidos
Fil: Camoin, Luc. Inserm; Francia
Fil: Estaras, Matias. Inserm; Francia
Fil: Brenière, Manon. Inserm; Francia
Fil: Modesti, Mauro. Inserm; Francia
Fil: Lomberk, Gwen. Medical College Of Wisconsin; Estados Unidos
Fil: Urrutia, Raul. Medical College Of Wisconsin; Estados Unidos
Fil: Soubeyran, Philippe. Inserm; Francia
Fil: Neira, Jose Luis. Inserm; Francia
Fil: Iovanna, Juan. Inserm; Francia
Materia
PANCREATIC CANCER
NUPR1
ZZW-115
STRESS GRANULES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/275307
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/275307
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumorsSantofimia Castaño, PatriciaFraunhoffer Navarro, Nicolas AlejandroLiu, XiFernández Bessone, Ivándi Magliano, Marina PascaAudebert, StephaneCamoin, LucEstaras, MatiasBrenière, ManonModesti, MauroLomberk, GwenUrrutia, RaulSoubeyran, PhilippeNeira, Jose LuisIovanna, JuanPANCREATIC CANCERNUPR1ZZW-115STRESS GRANULEShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1We 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-KrasG12D (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.Fil: Santofimia Castaño, Patricia. Inserm; FranciaFil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Liu, Xi. Inserm; FranciaFil: Fernández Bessone, Iván. Inserm; FranciaFil: di Magliano, Marina Pasca. Michigan State University; Estados UnidosFil: Audebert, Stephane. Medical College Of Wisconsin; Estados UnidosFil: Camoin, Luc. Inserm; FranciaFil: Estaras, Matias. Inserm; FranciaFil: Brenière, Manon. Inserm; FranciaFil: Modesti, Mauro. Inserm; FranciaFil: Lomberk, Gwen. Medical College Of Wisconsin; Estados UnidosFil: Urrutia, Raul. Medical College Of Wisconsin; Estados UnidosFil: Soubeyran, Philippe. Inserm; FranciaFil: Neira, Jose Luis. Inserm; FranciaFil: Iovanna, Juan. Inserm; FranciaWiley Blackwell Publishing, Inc2024-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/275307Santofimia Castaño, Patricia; Fraunhoffer Navarro, Nicolas Alejandro; Liu, Xi; Fernández Bessone, Iván; di Magliano, Marina Pasca; et al.; Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors; Wiley Blackwell Publishing, Inc; EMBO Molecular Medicine; 16; 3; 2-2024; 475-5051757-4684CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.embopress.org/doi/full/10.1038/s44321-024-00032-2info:eu-repo/semantics/altIdentifier/doi/10.1038/s44321-024-00032-2info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-12-03T09:08:03Zoai:ri.conicet.gov.ar:11336/275307instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-12-03 09:08:04.013CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors
title Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors
spellingShingle Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors
Santofimia Castaño, Patricia
PANCREATIC CANCER
NUPR1
ZZW-115
STRESS GRANULES
title_short 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_sort Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors
dc.creator.none.fl_str_mv Santofimia Castaño, Patricia
Fraunhoffer Navarro, Nicolas Alejandro
Liu, Xi
Fernández Bessone, Iván
di Magliano, Marina Pasca
Audebert, Stephane
Camoin, Luc
Estaras, Matias
Brenière, Manon
Modesti, Mauro
Lomberk, Gwen
Urrutia, Raul
Soubeyran, Philippe
Neira, Jose Luis
Iovanna, Juan
author Santofimia Castaño, Patricia
author_facet Santofimia Castaño, Patricia
Fraunhoffer Navarro, Nicolas Alejandro
Liu, Xi
Fernández Bessone, Iván
di Magliano, Marina Pasca
Audebert, Stephane
Camoin, Luc
Estaras, Matias
Brenière, Manon
Modesti, Mauro
Lomberk, Gwen
Urrutia, Raul
Soubeyran, Philippe
Neira, Jose Luis
Iovanna, Juan
author_role author
author2 Fraunhoffer Navarro, Nicolas Alejandro
Liu, Xi
Fernández Bessone, Iván
di Magliano, Marina Pasca
Audebert, Stephane
Camoin, Luc
Estaras, Matias
Brenière, Manon
Modesti, Mauro
Lomberk, Gwen
Urrutia, Raul
Soubeyran, Philippe
Neira, Jose Luis
Iovanna, Juan
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PANCREATIC CANCER
NUPR1
ZZW-115
STRESS GRANULES
topic PANCREATIC CANCER
NUPR1
ZZW-115
STRESS GRANULES
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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-KrasG12D (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.
Fil: Santofimia Castaño, Patricia. Inserm; Francia
Fil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Liu, Xi. Inserm; Francia
Fil: Fernández Bessone, Iván. Inserm; Francia
Fil: di Magliano, Marina Pasca. Michigan State University; Estados Unidos
Fil: Audebert, Stephane. Medical College Of Wisconsin; Estados Unidos
Fil: Camoin, Luc. Inserm; Francia
Fil: Estaras, Matias. Inserm; Francia
Fil: Brenière, Manon. Inserm; Francia
Fil: Modesti, Mauro. Inserm; Francia
Fil: Lomberk, Gwen. Medical College Of Wisconsin; Estados Unidos
Fil: Urrutia, Raul. Medical College Of Wisconsin; Estados Unidos
Fil: Soubeyran, Philippe. Inserm; Francia
Fil: Neira, Jose Luis. Inserm; Francia
Fil: Iovanna, Juan. Inserm; Francia
description 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-KrasG12D (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.
publishDate 2024
dc.date.none.fl_str_mv 2024-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/275307
Santofimia Castaño, Patricia; Fraunhoffer Navarro, Nicolas Alejandro; Liu, Xi; Fernández Bessone, Iván; di Magliano, Marina Pasca; et al.; Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors; Wiley Blackwell Publishing, Inc; EMBO Molecular Medicine; 16; 3; 2-2024; 475-505
1757-4684
CONICET Digital
CONICET
url http://hdl.handle.net/11336/275307
identifier_str_mv Santofimia Castaño, Patricia; Fraunhoffer Navarro, Nicolas Alejandro; Liu, Xi; Fernández Bessone, Iván; di Magliano, Marina Pasca; et al.; Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors; Wiley Blackwell Publishing, Inc; EMBO Molecular Medicine; 16; 3; 2-2024; 475-505
1757-4684
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.embopress.org/doi/full/10.1038/s44321-024-00032-2
info:eu-repo/semantics/altIdentifier/doi/10.1038/s44321-024-00032-2
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.214268

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