p140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response
Vincenzo Salemme, Mauro Vedelago, Alessandro Sarcinella, Federico Moietta, Alessio Piccolantonio, Enrico Moiso, Giorgia Centonze, Marta Manco, Andrea Guala, Alessia Lamolinara, Costanza Angelini, Alessandro Morellato, Dora Natalini, Raffaele Calogero, Danny Incarnato, Salvatore Oliviero, Laura Conti, Manuela Iezzi, Daniela Tosoni, Giovanni Bertalot, Stefano Freddi, Francesco Tucci, Francesco De Sanctis, Cristina Frusteri, Stefano Ugel, Vincenzo Bronte, Federica Cavallo, Paolo Provero, Marta Gai, Daniela Taverna, Emilia Turco, Salvatore Pece, Paola Defilippi
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.