Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP inhibition
Abstract Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61422-9 |
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| author | Siddhartha Mukherjee Cindy Garda Letizia Boffa Angela Rita Elia Matteo Massara Maria Teresa Balia Daniela Brina Simone Mosole Anna Campagnari Giada Andrea Cassanmagnago Andrea Rinaldi Giacomo Lazzaroni David Jarrossay Diego Morone Ilaria Ceppi Riccardo De Sillo Isabella Giacomini Ilaria Craparotta Laura Di Rito Simon Barry Endre Laczko Sebastian Streb Francesco Meani Simona Di Lascio Nancy Hynes Enrico Lugli Simone Puccio Stephen-John Sammut Ulrike Perriard Yves Harder Lorenzo Rossi Maria Luisa Gasparri Marco Bolis Petr Cejka Arianna Calcinotto |
| author_facet | Siddhartha Mukherjee Cindy Garda Letizia Boffa Angela Rita Elia Matteo Massara Maria Teresa Balia Daniela Brina Simone Mosole Anna Campagnari Giada Andrea Cassanmagnago Andrea Rinaldi Giacomo Lazzaroni David Jarrossay Diego Morone Ilaria Ceppi Riccardo De Sillo Isabella Giacomini Ilaria Craparotta Laura Di Rito Simon Barry Endre Laczko Sebastian Streb Francesco Meani Simona Di Lascio Nancy Hynes Enrico Lugli Simone Puccio Stephen-John Sammut Ulrike Perriard Yves Harder Lorenzo Rossi Maria Luisa Gasparri Marco Bolis Petr Cejka Arianna Calcinotto |
| author_sort | Siddhartha Mukherjee |
| collection | DOAJ |
| description | Abstract Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutic opportunities. Here, we identify a subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in highly proliferative hormone-dependent breast cancers and impair DNA repair capacity. Mechanistically, succinate secreted by tumor-associated PreNeu inhibits homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire genomic instability promoting tumor editing and progression. Selective inhibition of these pathways induces increased tumor cell killing in vitro and in vivo. Tumor-associated PreNeu score correlates with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumoral effect of these neutrophils and synergize with endocrine therapy. |
| format | Article |
| id | doaj-art-58e1738b598243218b9ea959684def1a |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-58e1738b598243218b9ea959684def1a2025-08-20T03:42:55ZengNature PortfolioNature Communications2041-17232025-07-0116112010.1038/s41467-025-61422-9Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP inhibitionSiddhartha Mukherjee0Cindy Garda1Letizia Boffa2Angela Rita Elia3Matteo Massara4Maria Teresa Balia5Daniela Brina6Simone Mosole7Anna Campagnari8Giada Andrea Cassanmagnago9Andrea Rinaldi10Giacomo Lazzaroni11David Jarrossay12Diego Morone13Ilaria Ceppi14Riccardo De Sillo15Isabella Giacomini16Ilaria Craparotta17Laura Di Rito18Simon Barry19Endre Laczko20Sebastian Streb21Francesco Meani22Simona Di Lascio23Nancy Hynes24Enrico Lugli25Simone Puccio26Stephen-John Sammut27Ulrike Perriard28Yves Harder29Lorenzo Rossi30Maria Luisa Gasparri31Marco Bolis32Petr Cejka33Arianna Calcinotto34Institute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute for Research in Biomedicine (IRB)Institute for Research in Biomedicine (IRB)Institute for Research in Biomedicine (IRB)Institute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandComputational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCSInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandBioscience, Early Oncology, AstraZenecaFunctional Genomics Center Zurich, ETH ZurichFunctional Genomics Center Zurich, ETH ZurichDepartment of Gynecology and Obstetrics, Centro di Senologia della Svizzera Italiana, Ente Ospedaliero CantonaleEnte Ospedaliero Cantonale Senology Center of Italian SwitzerlandFriedrich Miescher Institute for Biomedical ResearchIRCCS Humanitas Research HospitalIRCCS Humanitas Research HospitalThe Institute of Cancer Research and The Royal Marsden NHS Foundation TrustDepartment of Pathology, Locarno, Ente Ospedaliero CantonaleUniversità della Svizzera italiana, Faculty of Biomedical SciencesEnte Ospedaliero Cantonale Senology Center of Italian SwitzerlandDepartment of Gynecology and Obstetrics, Centro di Senologia della Svizzera Italiana, Ente Ospedaliero CantonaleInstitute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandInstitute for Research in Biomedicine (IRB)Institute of Oncology Research (IOR), Oncology Institute of Southern SwitzerlandAbstract Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutic opportunities. Here, we identify a subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in highly proliferative hormone-dependent breast cancers and impair DNA repair capacity. Mechanistically, succinate secreted by tumor-associated PreNeu inhibits homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire genomic instability promoting tumor editing and progression. Selective inhibition of these pathways induces increased tumor cell killing in vitro and in vivo. Tumor-associated PreNeu score correlates with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumoral effect of these neutrophils and synergize with endocrine therapy.https://doi.org/10.1038/s41467-025-61422-9 |
| spellingShingle | Siddhartha Mukherjee Cindy Garda Letizia Boffa Angela Rita Elia Matteo Massara Maria Teresa Balia Daniela Brina Simone Mosole Anna Campagnari Giada Andrea Cassanmagnago Andrea Rinaldi Giacomo Lazzaroni David Jarrossay Diego Morone Ilaria Ceppi Riccardo De Sillo Isabella Giacomini Ilaria Craparotta Laura Di Rito Simon Barry Endre Laczko Sebastian Streb Francesco Meani Simona Di Lascio Nancy Hynes Enrico Lugli Simone Puccio Stephen-John Sammut Ulrike Perriard Yves Harder Lorenzo Rossi Maria Luisa Gasparri Marco Bolis Petr Cejka Arianna Calcinotto Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP inhibition Nature Communications |
| title | Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP inhibition |
| title_full | Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP inhibition |
| title_fullStr | Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP inhibition |
| title_full_unstemmed | Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP inhibition |
| title_short | Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP inhibition |
| title_sort | tumor associated neutrophil precursors impair homologous dna repair and promote sensitivity to parp inhibition |
| url | https://doi.org/10.1038/s41467-025-61422-9 |
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