The p140Cap adaptor protein is a tumor suppressor in breast cancer associated with a favorable prognosis. Here we highlight a function of p140Cap in orchestrating local and systemic tumor-extrinsic events that eventually result in inhibition of the polymorphonuclear myeloid-derived suppressor cell function in creating an immunosuppressive tumor-promoting environment in the primary tumor, and premetastatic niches at distant sites. Integrative transcriptomic and preclinical studies unravel that p140Cap controls an epistatic axis where, through the upstream inhibition of β-Catenin, it restricts tumorigenicity and self-renewal of tumor-initiating cells limiting the release of the inflammatory cytokine G-CSF, required for polymorphonuclear myeloid-derived suppressor cells to exert their local and systemic tumor conducive function. Mechanistically, p140Cap inhibition of β-Catenin depends on its ability to localize in and stabilize the β-Catenin destruction complex, promoting enhanced β-Catenin inactivation. Clinical studies in women show that low p140Cap expression correlates with reduced presence of tumor-infiltrating lymphocytes and more aggressive tumor types in a large cohort of real-life female breast cancer patients, highlighting the potential of p140Cap as a biomarker for therapeutic intervention targeting the β-Catenin/ Tumor-initiating cells /G-CSF/ polymorphonuclear myeloid-derived suppressor cell axis to restore an efficient anti-tumor immune response

p140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response

Salemme, Vincenzo
First
;
Vedelago, Mauro;Sarcinella, Alessandro;Moietta, Federico;Moiso, Enrico;Centonze, Giorgia;Manco, Marta;Guala, Andrea;Angelini, Costanza;Morellato, Alessandro;Natalini, Dora;Calogero, Raffaele;Incarnato, Danny;Oliviero, Salvatore;Conti, Laura;Tucci, Francesco A;Cavallo, Federica;Provero, Paolo;Gai, Marta;Taverna, Daniela;Defilippi, Paola
2023-01-01

Abstract

The p140Cap adaptor protein is a tumor suppressor in breast cancer associated with a favorable prognosis. Here we highlight a function of p140Cap in orchestrating local and systemic tumor-extrinsic events that eventually result in inhibition of the polymorphonuclear myeloid-derived suppressor cell function in creating an immunosuppressive tumor-promoting environment in the primary tumor, and premetastatic niches at distant sites. Integrative transcriptomic and preclinical studies unravel that p140Cap controls an epistatic axis where, through the upstream inhibition of β-Catenin, it restricts tumorigenicity and self-renewal of tumor-initiating cells limiting the release of the inflammatory cytokine G-CSF, required for polymorphonuclear myeloid-derived suppressor cells to exert their local and systemic tumor conducive function. Mechanistically, p140Cap inhibition of β-Catenin depends on its ability to localize in and stabilize the β-Catenin destruction complex, promoting enhanced β-Catenin inactivation. Clinical studies in women show that low p140Cap expression correlates with reduced presence of tumor-infiltrating lymphocytes and more aggressive tumor types in a large cohort of real-life female breast cancer patients, highlighting the potential of p140Cap as a biomarker for therapeutic intervention targeting the β-Catenin/ Tumor-initiating cells /G-CSF/ polymorphonuclear myeloid-derived suppressor cell axis to restore an efficient anti-tumor immune response
2023
14
1
2350
2371
https://pubmed.ncbi.nlm.nih.gov/37169737/
breast cancer; p140Cap
Salemme, Vincenzo; Vedelago, Mauro; Sarcinella, Alessandro; Moietta, Federico; Piccolantonio, Alessio; Moiso, Enrico; Centonze, Giorgia; Manco, Marta; Guala, Andrea; Lamolinara, Alessia; Angelini, Costanza; Morellato, Alessandro; Natalini, Dora; Calogero, Raffaele; Incarnato, Danny; Oliviero, Salvatore; Conti, Laura; Iezzi, Manuela; Tosoni, Daniela; Bertalot, Giovanni; Freddi, Stefano; Tucci, Francesco A; De Sanctis, Francesco; Frusteri, Cristina; Ugel, Stefano; Bronte, Vincenzo; Cavallo, Federica; Provero, Paolo; Gai, Marta; Taverna, Daniela; Turco, Emilia; Pece, Salvatore; Defilippi, Paola
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1927550
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