Prune-1 drives polarization of tumor-associated macrophages (TAMs) within the lung metastatic niche in triple-negative breast cancer

Veronica Ferrucci; Fatemeh Asadzadeh; Francesca Collina; Roberto Siciliano; Angelo Boccia; Laura Marrone; Daniela Spano; Marianeve Carotenuto; Cristina Maria Chiarolla; Daniela De Martino; Gennaro De Vita; Alessandra Macrì; Luisa Dassi; Jonathan Vandenbussche; Natascia Marino; Monica Cantile; Giovanni Paolella; Francesco D'Andrea; Maurizio di Bonito; Kris Gevaert; Massimo Zollo

doi:10.1016/j.isci.2020.101938

Prune-1 drives polarization of tumor-associated macrophages (TAMs) within the lung metastatic niche in triple-negative breast cancer

iScience. 2020 Dec 13;24(1):101938. doi: 10.1016/j.isci.2020.101938. eCollection 2021 Jan 22.

Authors

Veronica Ferrucci^{1

2

3}, Fatemeh Asadzadeh^{1

2}, Francesca Collina⁴, Roberto Siciliano¹, Angelo Boccia¹, Laura Marrone^{1

2}, Daniela Spano¹, Marianeve Carotenuto², Cristina Maria Chiarolla¹, Daniela De Martino², Gennaro De Vita², Alessandra Macrì¹, Luisa Dassi¹, Jonathan Vandenbussche^{5

6}, Natascia Marino^{1

7}, Monica Cantile⁴, Giovanni Paolella¹, Francesco D'Andrea⁸, Maurizio di Bonito⁴, Kris Gevaert^{5

6}, Massimo Zollo^{1

2

3

9}

Affiliations

¹ CEINGE, Biotecnologie Avanzate, Naples 80145, Italy.
² Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), 'Federico II' University of Naples, Naples 80134, Italy.
³ European School of Molecular Medicine (SEMM), University of Milan, Milan, Italy.
⁴ Pathology Unit, Istituto Nazionale Tumori-IRCS- Fondazione G.Pascale, Naples 80131, Italy.
⁵ VIB-UGent Centre for Medical Biotechnology, Ghent 9052, Belgium.
⁶ Department of Biomolecular Medicine, Ghent University, B9052 Ghent, Belgium.
⁷ Department of Medicine, Indiana University-Purdue University Indianapolis, Indianapolis 46202, USA.
⁸ Dipartimento di Sanità pubblica - AOU, Università; degli Studi di Napoli Federico II, Naples 80131, Italy.
⁹ DAI Medicina di Laboratorio e Trasfusionale, AOU Federico II, Naples 80131, Italy.

Abstract

M2-tumor-associated macrophages (M2-TAMs) in the tumor microenvironment represent a prognostic indicator for poor outcome in triple-negative breast cancer (TNBC). Here we show that Prune-1 overexpression in human TNBC patients has positive correlation to lung metastasis and infiltrating M2-TAMs. Thus, we demonstrate that Prune-1 promotes lung metastasis in a genetically engineered mouse model of metastatic TNBC augmenting M2-polarization of TAMs within the tumor microenvironment. Thus, this occurs through TGF-β enhancement, IL-17F secretion, and extracellular vesicle protein content modulation. We also find murine inactivating gene variants in human TNBC patient cohorts that are involved in activation of the innate immune response, cell adhesion, apoptotic pathways, and DNA repair. Altogether, we indicate that the overexpression of Prune-1, IL-10, COL4A1, ILR1, and PDGFB, together with inactivating mutations of PDE9A, CD244, Sirpb1b, SV140, Iqca1, and PIP5K1B genes, might represent a route of metastatic lung dissemination that need future prognostic validations.

Keywords: Cancer; Immunology; Molecular Biology.