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<p>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.</p>

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Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月30日

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  • 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

摘要

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.