Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Monteiro, Cátia; Miarka, Lauritz; Perea-García, María; Priego, Neibla; García-Gómez, Pedro; Álvaro-Espinosa, Laura; Pablos-Aragoneses, Ana de; Yebra, Natalia; Retana, Diana; Baena, Patricia; Fustero-Torre, Coral; Graña-Castro, Osvaldo; Troulé, Kevin; Caleiras, Eduardo; Tezanos, Patricia; Muela, Pablo; Cintado, Elisa; Trejo, José Luis; Sepúlveda-Sánchez, Juan Manuel; González-León, Pedro; Jiménez-Roldán, Luis; Moreno, Luis Miguel; Esteban, Olga; Pérez-Núñez, Ángel; Hernández-Lain, Aurelio; Mazarico Gallego, José; Ferrer, Irene; Suárez, Rocío; Garrido-Martín, Eva M.; Paz-Ares, Luis; Dalmasso, Celine; Cohen-Jonathan Moyal, Elizabeth; Siegfried, Aurore; Hegarty, Aisling; Keelan, Stephen; Vare lija, Damir; Young, Leonie S.; Mohme, Malte; Goy, Yvonne; Wikman, Harriet; Fernández-Alén, Jose; Blasco, Guillermo; Alcázar, Lucía; Cabañuz, Clara; Grivennikov, Sergei I.; Ianus, Andrada; Shemesh, Noam; Faria, Claudia C.; Lee, Rebecca; Lorigan, Paul; Le Rhun, Emilie; Weller, Michael; Soffietti, Riccardo; Bertero, Luca; Ricardi, Umberto; Bosch Barrera, Joaquim; Sais, Elia; Teixidor, Eduard; Hernández-Martínez, Alejandro; Calvo, Alfonso; Aristu, Javier; Martin, Santiago M.; Gonzalez, Alvaro; Adler, Omer; Erez, Neta; Valiente Malmagro, Manuel

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the li...

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Authors:	Monteiro, Cátia, Miarka, Lauritz, Perea-García, María, Priego, Neibla, García-Gómez, Pedro, Álvaro-Espinosa, Laura, Pablos-Aragoneses, Ana de, Yebra, Natalia, Retana, Diana, Baena, Patricia, Fustero-Torre, Coral, Graña-Castro, Osvaldo, Troulé, Kevin, Caleiras, Eduardo, Tezanos, Patricia, Muela, Pablo, Cintado, Elisa, Trejo, José Luis, Sepúlveda-Sánchez, Juan Manuel, González-León, Pedro, Jiménez-Roldán, Luis, Moreno, Luis Miguel, Esteban, Olga, Pérez-Núñez, Ángel, Hernández-Lain, Aurelio, Mazarico Gallego, José, Ferrer, Irene, Suárez, Rocío, Garrido-Martín, Eva M., Paz-Ares, Luis, Dalmasso, Celine, Cohen-Jonathan Moyal, Elizabeth, Siegfried, Aurore, Hegarty, Aisling, Keelan, Stephen, Vare lija, Damir, Young, Leonie S., Mohme, Malte, Goy, Yvonne, Wikman, Harriet, Fernández-Alén, Jose, Blasco, Guillermo, Alcázar, Lucía, Cabañuz, Clara, Grivennikov, Sergei I., Ianus, Andrada, Shemesh, Noam, Faria, Claudia C., Lee, Rebecca, Lorigan, Paul, Le Rhun, Emilie, Weller, Michael, Soffietti, Riccardo, Bertero, Luca, Ricardi, Umberto, Bosch Barrera, Joaquim, Sais, Elia, Teixidor, Eduard, Hernández-Martínez, Alejandro, Calvo, Alfonso, Aristu, Javier, Martin, Santiago M., Gonzalez, Alvaro, Adler, Omer, Erez, Neta, Valiente Malmagro, Manuel
Format:	article
Status:	Versión aceptada para publicación
Publication Date:	2022
Country:	España
Institution:	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:	Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:	oai:recercat.cat:10256/25131
Online Access:	http://hdl.handle.net/10256/25131
Access Level:	Open access
Keyword:	Pulmons -- Càncer Lungs -- Cancer Metàstasi Metastasis Radiocirurgia Radiosurgery

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oai_identifier_str	oai:recercat.cat:10256/25131
network_acronym_str	ES
network_name_str	España
repository_id_str
dc.title.none.fl_str_mv	Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism
title	Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism
spellingShingle	Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism Monteiro, Cátia Pulmons -- Càncer Lungs -- Cancer Metàstasi Metastasis Radiocirurgia Radiosurgery
title_short	Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism
title_full	Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism
title_fullStr	Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism
title_full_unstemmed	Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism
title_sort	Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism
dc.creator.none.fl_str_mv	Monteiro, Cátia Miarka, Lauritz Perea-García, María Priego, Neibla García-Gómez, Pedro Álvaro-Espinosa, Laura Pablos-Aragoneses, Ana de Yebra, Natalia Retana, Diana Baena, Patricia Fustero-Torre, Coral Graña-Castro, Osvaldo Troulé, Kevin Caleiras, Eduardo Tezanos, Patricia Muela, Pablo Cintado, Elisa Trejo, José Luis Sepúlveda-Sánchez, Juan Manuel González-León, Pedro Jiménez-Roldán, Luis Moreno, Luis Miguel Esteban, Olga Pérez-Núñez, Ángel Hernández-Lain, Aurelio Mazarico Gallego, José Ferrer, Irene Suárez, Rocío Garrido-Martín, Eva M. Paz-Ares, Luis Dalmasso, Celine Cohen-Jonathan Moyal, Elizabeth Siegfried, Aurore Hegarty, Aisling Keelan, Stephen Vare lija, Damir Young, Leonie S. Mohme, Malte Goy, Yvonne Wikman, Harriet Fernández-Alén, Jose Blasco, Guillermo Alcázar, Lucía Cabañuz, Clara Grivennikov, Sergei I. Ianus, Andrada Shemesh, Noam Faria, Claudia C. Lee, Rebecca Lorigan, Paul Le Rhun, Emilie Weller, Michael Soffietti, Riccardo Bertero, Luca Ricardi, Umberto Bosch Barrera, Joaquim Sais, Elia Teixidor, Eduard Hernández-Martínez, Alejandro Calvo, Alfonso Aristu, Javier Martin, Santiago M. Gonzalez, Alvaro Adler, Omer Erez, Neta Valiente Malmagro, Manuel
author	Monteiro, Cátia
author_facet	Monteiro, Cátia Miarka, Lauritz Perea-García, María Priego, Neibla García-Gómez, Pedro Álvaro-Espinosa, Laura Pablos-Aragoneses, Ana de Yebra, Natalia Retana, Diana Baena, Patricia Fustero-Torre, Coral Graña-Castro, Osvaldo Troulé, Kevin Caleiras, Eduardo Tezanos, Patricia Muela, Pablo Cintado, Elisa Trejo, José Luis Sepúlveda-Sánchez, Juan Manuel González-León, Pedro Jiménez-Roldán, Luis Moreno, Luis Miguel Esteban, Olga Pérez-Núñez, Ángel Hernández-Lain, Aurelio Mazarico Gallego, José Ferrer, Irene Suárez, Rocío Garrido-Martín, Eva M. Paz-Ares, Luis Dalmasso, Celine Cohen-Jonathan Moyal, Elizabeth Siegfried, Aurore Hegarty, Aisling Keelan, Stephen Vare lija, Damir Young, Leonie S. Mohme, Malte Goy, Yvonne Wikman, Harriet Fernández-Alén, Jose Blasco, Guillermo Alcázar, Lucía Cabañuz, Clara Grivennikov, Sergei I. Ianus, Andrada Shemesh, Noam Faria, Claudia C. Lee, Rebecca Lorigan, Paul Le Rhun, Emilie Weller, Michael Soffietti, Riccardo Bertero, Luca Ricardi, Umberto Bosch Barrera, Joaquim Sais, Elia Teixidor, Eduard Hernández-Martínez, Alejandro Calvo, Alfonso Aristu, Javier Martin, Santiago M. Gonzalez, Alvaro Adler, Omer Erez, Neta Valiente Malmagro, Manuel
author_role	author
author2	Miarka, Lauritz Perea-García, María Priego, Neibla García-Gómez, Pedro Álvaro-Espinosa, Laura Pablos-Aragoneses, Ana de Yebra, Natalia Retana, Diana Baena, Patricia Fustero-Torre, Coral Graña-Castro, Osvaldo Troulé, Kevin Caleiras, Eduardo Tezanos, Patricia Muela, Pablo Cintado, Elisa Trejo, José Luis Sepúlveda-Sánchez, Juan Manuel González-León, Pedro Jiménez-Roldán, Luis Moreno, Luis Miguel Esteban, Olga Pérez-Núñez, Ángel Hernández-Lain, Aurelio Mazarico Gallego, José Ferrer, Irene Suárez, Rocío Garrido-Martín, Eva M. Paz-Ares, Luis Dalmasso, Celine Cohen-Jonathan Moyal, Elizabeth Siegfried, Aurore Hegarty, Aisling Keelan, Stephen Vare lija, Damir Young, Leonie S. Mohme, Malte Goy, Yvonne Wikman, Harriet Fernández-Alén, Jose Blasco, Guillermo Alcázar, Lucía Cabañuz, Clara Grivennikov, Sergei I. Ianus, Andrada Shemesh, Noam Faria, Claudia C. Lee, Rebecca Lorigan, Paul Le Rhun, Emilie Weller, Michael Soffietti, Riccardo Bertero, Luca Ricardi, Umberto Bosch Barrera, Joaquim Sais, Elia Teixidor, Eduard Hernández-Martínez, Alejandro Calvo, Alfonso Aristu, Javier Martin, Santiago M. Gonzalez, Alvaro Adler, Omer Erez, Neta Valiente Malmagro, Manuel
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Pulmons -- Càncer Lungs -- Cancer Metàstasi Metastasis Radiocirurgia Radiosurgery
topic	Pulmons -- Càncer Lungs -- Cancer Metàstasi Metastasis Radiocirurgia Radiosurgery
description	Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity
publishDate	2022
dc.date.none.fl_str_mv	2022
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion peer-reviewed
format	article
status_str	acceptedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10256/25131
url	http://hdl.handle.net/10256/25131
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	info:eu-repo/semantics/altIdentifier/doi/10.1038/s41591-022-01749-8 info:eu-repo/semantics/altIdentifier/issn/1078-8956 info:eu-repo/semantics/altIdentifier/eissn/1546-170X
dc.rights.none.fl_str_mv	Reconeixement 4.0 Internacional http://creativecommons.org/licenses/by/4.0 info:eu-repo/semantics/openAccess
rights_invalid_str_mv	Reconeixement 4.0 Internacional http://creativecommons.org/licenses/by/4.0
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	14 p. application/pdf
dc.publisher.none.fl_str_mv	Nature Research
publisher.none.fl_str_mv	Nature Research
dc.source.none.fl_str_mv	Nature Medicine, 2022, vol. 28, num. 4, p. 752-765 Articles publicats (D-CM) Monteiro, Cátia Miarka, Lauritz Perea-García, María Priego, Neibla García-Gómez, Pedro Álvaro-Espinosa, Laura Pablos-Aragoneses, Ana de Yebra, Natalia Retana, Diana Baena, Patricia Fustero-Torre, Coral Graña-Castro, Osvaldo Troulé, Kevin Caleiras, Eduardo Tezanos, Patricia Muela, Pablo Cintado, Elisa Trejo, José Luis Sepúlveda-Sánchez, Juan Manuel González-León, Pedro Jiménez-Roldán, Luis Moreno, Luis Miguel Esteban, Olga Pérez-Núñez, Ángel Hernández-Lain, Aurelio Mazarico Gallego, José Ferrer, Irene Suárez, Rocío Garrido-Martín, Eva M. Paz-Ares, Luis Dalmasso, Celine Cohen-Jonathan Moyal, Elizabeth Siegfried, Aurore Hegarty, Aisling Keelan, Stephen Vare lija, Damir Young, Leonie S. Mohme, Malte Goy, Yvonne Wikman, Harriet 2022 Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism Nature Medicine 28 4 752 765 reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str	Recercat. Dipósit de la Recerca de Catalunya
collection	Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling	Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanismMonteiro, CátiaMiarka, LauritzPerea-García, MaríaPriego, NeiblaGarcía-Gómez, PedroÁlvaro-Espinosa, LauraPablos-Aragoneses, Ana deYebra, NataliaRetana, DianaBaena, PatriciaFustero-Torre, CoralGraña-Castro, OsvaldoTroulé, KevinCaleiras, EduardoTezanos, PatriciaMuela, PabloCintado, ElisaTrejo, José LuisSepúlveda-Sánchez, Juan ManuelGonzález-León, PedroJiménez-Roldán, LuisMoreno, Luis MiguelEsteban, OlgaPérez-Núñez, ÁngelHernández-Lain, AurelioMazarico Gallego, JoséFerrer, IreneSuárez, RocíoGarrido-Martín, Eva M.Paz-Ares, LuisDalmasso, CelineCohen-Jonathan Moyal, ElizabethSiegfried, AuroreHegarty, AislingKeelan, StephenVare lija, DamirYoung, Leonie S.Mohme, MalteGoy, YvonneWikman, HarrietFernández-Alén, JoseBlasco, GuillermoAlcázar, LucíaCabañuz, ClaraGrivennikov, Sergei I.Ianus, AndradaShemesh, NoamFaria, Claudia C.Lee, RebeccaLorigan, PaulLe Rhun, EmilieWeller, MichaelSoffietti, RiccardoBertero, LucaRicardi, UmbertoBosch Barrera, JoaquimSais, EliaTeixidor, EduardHernández-Martínez, AlejandroCalvo, AlfonsoAristu, JavierMartin, Santiago M.Gonzalez, AlvaroAdler, OmerErez, NetaValiente Malmagro, ManuelPulmons -- CàncerLungs -- CancerMetàstasiMetastasisRadiocirurgiaRadiosurgeryWhole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicityNature Research2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionpeer-reviewed14 p.application/pdfhttp://hdl.handle.net/10256/25131Nature Medicine, 2022, vol. 28, num. 4, p. 752-765Articles publicats (D-CM)Monteiro, Cátia Miarka, Lauritz Perea-García, María Priego, Neibla García-Gómez, Pedro Álvaro-Espinosa, Laura Pablos-Aragoneses, Ana de Yebra, Natalia Retana, Diana Baena, Patricia Fustero-Torre, Coral Graña-Castro, Osvaldo Troulé, Kevin Caleiras, Eduardo Tezanos, Patricia Muela, Pablo Cintado, Elisa Trejo, José Luis Sepúlveda-Sánchez, Juan Manuel González-León, Pedro Jiménez-Roldán, Luis Moreno, Luis Miguel Esteban, Olga Pérez-Núñez, Ángel Hernández-Lain, Aurelio Mazarico Gallego, José Ferrer, Irene Suárez, Rocío Garrido-Martín, Eva M. Paz-Ares, Luis Dalmasso, Celine Cohen-Jonathan Moyal, Elizabeth Siegfried, Aurore Hegarty, Aisling Keelan, Stephen Vare lija, Damir Young, Leonie S. Mohme, Malte Goy, Yvonne Wikman, Harriet 2022 Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism Nature Medicine 28 4 752 765reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41591-022-01749-8info:eu-repo/semantics/altIdentifier/issn/1078-8956info:eu-repo/semantics/altIdentifier/eissn/1546-170XReconeixement 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0info:eu-repo/semantics/openAccessoai:recercat.cat:10256/251312026-05-29T05:05:01Z
score	15,812429

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

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