TY - JOUR
T1 - Prune-1 drives polarization of tumor-associated macrophages (TAMs) within the lung metastatic niche in triple-negative breast cancer
AU - Ferrucci, Veronica
AU - Asadzadeh, Fatemeh
AU - Collina, Francesca
AU - Siciliano, Roberto
AU - Boccia, Angelo
AU - Marrone, Laura
AU - Spano, Daniela
AU - Carotenuto, Marianeve
AU - Chiarolla, Cristina Maria
AU - De Martino, Daniela
AU - De Vita, Gennaro
AU - Macrì, Alessandra
AU - Dassi, Luisa
AU - Vandenbussche, Jonathan
AU - Marino, Natascia
AU - Cantile, Monica
AU - Paolella, Giovanni
AU - D'Andrea, Francesco
AU - di Bonito, Maurizio
AU - Gevaert, Kris
AU - Zollo, Massimo
N1 - Funding Information:
We thank Prof. John Collard (NCI Amsterdam, The Netherlands) for supporting the project by sharing the mouse MMTV?Wnt1 model, and we are grateful for his comments and fruitful discussions about these research findings. We thank Prof. Ettore Capoluongo (University of Naples Federico II/ CEINGE/ DAI AOU Federico II Medicina di laboratorio e Trasfusionale) for helpfull discussion related to the prognostic value of our results. The authors thank the following resources agencies for grant support: Sviluppo di Approcci Terapeutici INnovativi per patologie neoplastiche resistenti ai trattamenti ? SATIN D.D. n. 355 del 5/06/2017 (MZ), EU-FP7-TUMIC-HEALTH-F2-2008-2016662 (MZ), the Italian Association for Cancer Research (AIRC) Grant IG #22129 (MZ), the Regione Campania L.g.R: N.5 (MZ), the European National Funds PON01-02388/1 2007-2013 (MZ), POR Rete delle Biotecnologie in Campania Movie (MZ), the European infrastructure for proteomics PRIME-XS-000016, the European School of Molecular Medicine for a Fellowship (VF), Fondazione Celeghin Italiana (MZ), and The European Mutant Mouse Archive (EMMA) for deposition of the transgenic mouse model MMTV?Prune-1 [code: FVB-Tg(MMTV?PRUNE)/Cnrm]. V.F. performed in-vitro co-culture experiments and EVs isolation. V.F. and L.M. performed immunoblotting analyses. F.A. and D.D.M. performed in-vivo trials. F.A. performed IF analyses. F.A. C.M.C. L.D. G.D.V. and A.M. performed quantitative IHC analyses. R.S. performed real-time RT-PCR assays. A.B. and G.P. analyzed RNAseq data. V.F. A.B. and G.P. analyzed WES data. D.S. monitored mice crossing. D.S. and M.C. generated cell clones and performed cytokines arrays. F.C. M.C. and M.D.B. performed TMA. J.V. and K.G. performed proteomic analyses. F.D.A. provided controls specimens. N.M. generated the MMTV?Prune-1/Wnt1 mouse. M.Z. designed the experiments and wrote the manuscript. All authors discussed the results and commented on, and approved, the manuscript. All the authors declare no competing financial interests.
Funding Information:
We thank Prof. John Collard (NCI Amsterdam, The Netherlands) for supporting the project by sharing the mouse MMTV–Wnt1 model, and we are grateful for his comments and fruitful discussions about these research findings. We thank Prof. Ettore Capoluongo (University of Naples Federico II/ CEINGE/ DAI AOU Federico II Medicina di laboratorio e Trasfusionale) for helpfull discussion related to the prognostic value of our results. The authors thank the following resources agencies for grant support: Sviluppo di Approcci Terapeutici INnovativi per patologie neoplastiche resistenti ai trattamenti – SATIN D.D. n. 355 del 5/06/2017 (MZ), EU-FP7-TUMIC-HEALTH-F2-2008-2016662 (MZ), the Italian Association for Cancer Research (AIRC) Grant IG #22129 (MZ), the Regione Campania L.g.R: N.5 (MZ), the European National Funds PON01-02388/1 2007-2013 (MZ), POR Rete delle Biotecnologie in Campania Movie (MZ), the European infrastructure for proteomics PRIME-XS-000016, the European School of Molecular Medicine for a Fellowship (VF), Fondazione Celeghin Italiana (MZ), and The European Mutant Mouse Archive (EMMA) for deposition of the transgenic mouse model MMTV–Prune-1 [code: FVB-Tg(MMTV–PRUNE)/Cnrm].
Publisher Copyright:
© 2020 The Author(s)
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/1/22
Y1 - 2021/1/22
N2 - 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.
AB - 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.
KW - Cancer
KW - Immunology
KW - Molecular Biology
UR - http://www.scopus.com/inward/record.url?scp=85098578691&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098578691&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2020.101938
DO - 10.1016/j.isci.2020.101938
M3 - Article
AN - SCOPUS:85098578691
VL - 24
JO - iScience
JF - iScience
SN - 2589-0042
IS - 1
M1 - 101938
ER -