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

• Published in: Nature communications 2023-05, Vol.14 (1), p.2350-2350, Article 2350
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/31; 13/44; 13/51; 13/95; 14; 14/19; 14/35; 631/67/327; 631/80/86/820; 692/4028/67/1347; 96; Adapters; beta Catenin - metabolism; Biomarkers; Breast - pathology; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Epistasis; Female; Granulocyte colony-stimulating factor; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunity; Inactivation; Inflammation; Lymphocytes; multidisciplinary; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - metabolism; Prognosis; Proteins; Science; Science (multidisciplinary); Stem cells; Suppressor cells; Transcriptomics; Tumor suppressor genes; Tumor-infiltrating lymphocytes; Tumorigenicity; Tumors; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37824-y

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. The p140Cap adaptor protein is a tumour suppressor associated with improved prognosis in breast cancer. Here, the authors identify a role for p140Cap in preventing the immunosuppressive and pro-tumour function of polymorphonuclear myeloid-derived suppressor cells via downmodulation of the β-Catenin/Tumor Initiating Cells/G-CSF axi