A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior

Irene Schiano Lomoriello; Giovanni Giangreco; Claudia Iavarone; Chiara Tordonato; Giusi Caldieri; Gaetana Serio; Stefano Confalonieri; Stefano Freddi; Fabrizio Bianchi; Stefania Pirroni; Giovanni Bertalot; Giuseppe Viale; Davide Disalvatore; Daniela Tosoni; Maria Grazia Malabarba; Andrea Disanza; Giorgio Scita; Salvatore Pece; Brian K. Pilcher; Manuela Vecchi; Sara Sigismund; Pier Paolo Di Fiore

doi:10.1038/s41467-020-16836-y

A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior

Irene Schiano Lomoriello, Giovanni Giangreco, Claudia Iavarone, Chiara Tordonato, Giusi Caldieri, Gaetana Serio, Stefano Confalonieri, Stefano Freddi, Fabrizio Bianchi, Stefania Pirroni, Giovanni Bertalot, Giuseppe Viale, Davide Disalvatore, Daniela Tosoni, Maria Grazia Malabarba, Andrea Disanza, Giorgio Scita, Salvatore Pece, Brian K. Pilcher, Manuela VecchiSara Sigismund, Pier Paolo Di Fiore

Istituto Europeo di Oncologia

Research output: Contribution to journal › Article › peer-review

Abstract

The subversion of endocytic routes leads to malignant transformation and has been implicated in human cancers. However, there is scarce evidence for genetic alterations of endocytic proteins as causative in high incidence human cancers. Here, we report that Epsin 3 (EPN3) is an oncogene with prognostic and therapeutic relevance in breast cancer. Mechanistically, EPN3 drives breast tumorigenesis by increasing E-cadherin endocytosis, followed by the activation of a β-catenin/TCF4-dependent partial epithelial-to-mesenchymal transition (EMT), followed by the establishment of a TGFβ-dependent autocrine loop that sustains EMT. EPN3-induced partial EMT is instrumental for the transition from in situ to invasive breast carcinoma, and, accordingly, high EPN3 levels are detected at the invasive front of human breast cancers and independently predict metastatic rather than loco-regional recurrence. Thus, we uncover an endocytic-based mechanism able to generate TGFβ-dependent regulatory loops conferring cellular plasticity and invasive behavior.

Original language	English
Article number	3020
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16836-y
Publication status	Published - Dec 1 2020

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Schiano Lomoriello, I., Giangreco, G., Iavarone, C., Tordonato, C., Caldieri, G., Serio, G., Confalonieri, S., Freddi, S., Bianchi, F., Pirroni, S., Bertalot, G., Viale, G., Disalvatore, D., Tosoni, D., Malabarba, M. G., Disanza, A., Scita, G., Pece, S., Pilcher, B. K., ... Di Fiore, P. P. (2020). A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior. Nature Communications, 11(1), [3020]. https://doi.org/10.1038/s41467-020-16836-y

A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior. / Schiano Lomoriello, Irene; Giangreco, Giovanni; Iavarone, Claudia ; Tordonato, Chiara ; Caldieri, Giusi; Serio, Gaetana; Confalonieri, Stefano ; Freddi, Stefano; Bianchi, Fabrizio; Pirroni, Stefania; Bertalot, Giovanni; Viale, Giuseppe; Disalvatore, Davide; Tosoni, Daniela ; Malabarba, Maria Grazia; Disanza, Andrea; Scita, Giorgio; Pece, Salvatore; Pilcher, Brian K.; Vecchi, Manuela; Sigismund, Sara ; Di Fiore, Pier Paolo.

In: Nature Communications, Vol. 11, No. 1, 3020, 01.12.2020.

Research output: Contribution to journal › Article › peer-review

Schiano Lomoriello, I, Giangreco, G, Iavarone, C , Tordonato, C , Caldieri, G, Serio, G, Confalonieri, S , Freddi, S, Bianchi, F, Pirroni, S, Bertalot, G, Viale, G, Disalvatore, D, Tosoni, D , Malabarba, MG, Disanza, A, Scita, G, Pece, S, Pilcher, BK, Vecchi, M, Sigismund, S & Di Fiore, PP 2020, 'A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior', Nature Communications, vol. 11, no. 1, 3020. https://doi.org/10.1038/s41467-020-16836-y

Schiano Lomoriello, Irene ; Giangreco, Giovanni ; Iavarone, Claudia ; Tordonato, Chiara ; Caldieri, Giusi ; Serio, Gaetana ; Confalonieri, Stefano ; Freddi, Stefano ; Bianchi, Fabrizio ; Pirroni, Stefania ; Bertalot, Giovanni ; Viale, Giuseppe ; Disalvatore, Davide ; Tosoni, Daniela ; Malabarba, Maria Grazia ; Disanza, Andrea ; Scita, Giorgio ; Pece, Salvatore ; Pilcher, Brian K. ; Vecchi, Manuela ; Sigismund, Sara ; Di Fiore, Pier Paolo. / A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior. In: Nature Communications. 2020 ; Vol. 11, No. 1.

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title = "A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior",

abstract = "The subversion of endocytic routes leads to malignant transformation and has been implicated in human cancers. However, there is scarce evidence for genetic alterations of endocytic proteins as causative in high incidence human cancers. Here, we report that Epsin 3 (EPN3) is an oncogene with prognostic and therapeutic relevance in breast cancer. Mechanistically, EPN3 drives breast tumorigenesis by increasing E-cadherin endocytosis, followed by the activation of a β-catenin/TCF4-dependent partial epithelial-to-mesenchymal transition (EMT), followed by the establishment of a TGFβ-dependent autocrine loop that sustains EMT. EPN3-induced partial EMT is instrumental for the transition from in situ to invasive breast carcinoma, and, accordingly, high EPN3 levels are detected at the invasive front of human breast cancers and independently predict metastatic rather than loco-regional recurrence. Thus, we uncover an endocytic-based mechanism able to generate TGFβ-dependent regulatory loops conferring cellular plasticity and invasive behavior.",

author = "{Schiano Lomoriello}, Irene and Giovanni Giangreco and Claudia Iavarone and Chiara Tordonato and Giusi Caldieri and Gaetana Serio and Stefano Confalonieri and Stefano Freddi and Fabrizio Bianchi and Stefania Pirroni and Giovanni Bertalot and Giuseppe Viale and Davide Disalvatore and Daniela Tosoni and Malabarba, {Maria Grazia} and Andrea Disanza and Giorgio Scita and Salvatore Pece and Pilcher, {Brian K.} and Manuela Vecchi and Sara Sigismund and {Di Fiore}, {Pier Paolo}",

note = "Funding Information: We thank Rosalind Gunby for critically reading the manuscript; Chiara Luise, Giovanna Jodice, and Barbara Giulini for technical assistance; Marilena Bicchieri for help with the mammosphere assay; Alberto Gobbi, Manuela Capillo, and the Mouse facility (Cogen-tech Societ{\`a} Benefit Srl, Milan) for mice handling; Tom Kirchhausen for reagents and suggestions. The results shown in Fig. 1b are in part based upon the data generated by the TCGA Research Network: http://cancergenome.nih.gov/. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC - IG 18988, IG 23060 to P.P.D.F. and MCO 10.000; IG 18621, IG 22821 and MultiUnit −5 per Mille-22759 to GS; IG 11904, IG 15538, and MCO 10.000 to S.P.); the Italian Ministry of University and Scientific Research (MIUR) to P.P.D.F. (Prot. 2015XS92CC); the Italian Ministry of Health to D.T. (RF-2013-02358446); the Worldwide Cancer Research (16-1245) to S.S.; the European Research Council (Advanced-ERC − 268836) to G.S.; the Cariplo Foundation (2008.2448 to M.V.; 2011-0596 to A.D.). G.G., I.S.L., and C.T. were supported by an AIRC fellowship. This work was also partially supported by the Italian Ministry of Health with Ricerca Corrente and 5 × 1000 funds. Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

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doi = "10.1038/s41467-020-16836-y",

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T1 - A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior

AU - Schiano Lomoriello, Irene

AU - Giangreco, Giovanni

AU - Iavarone, Claudia

AU - Tordonato, Chiara

AU - Caldieri, Giusi

AU - Serio, Gaetana

AU - Confalonieri, Stefano

AU - Freddi, Stefano

AU - Bianchi, Fabrizio

AU - Pirroni, Stefania

AU - Bertalot, Giovanni

AU - Viale, Giuseppe

AU - Disalvatore, Davide

AU - Tosoni, Daniela

AU - Malabarba, Maria Grazia

AU - Disanza, Andrea

AU - Scita, Giorgio

AU - Pece, Salvatore

AU - Pilcher, Brian K.

AU - Vecchi, Manuela

AU - Sigismund, Sara

AU - Di Fiore, Pier Paolo

N1 - Funding Information: We thank Rosalind Gunby for critically reading the manuscript; Chiara Luise, Giovanna Jodice, and Barbara Giulini for technical assistance; Marilena Bicchieri for help with the mammosphere assay; Alberto Gobbi, Manuela Capillo, and the Mouse facility (Cogen-tech Società Benefit Srl, Milan) for mice handling; Tom Kirchhausen for reagents and suggestions. The results shown in Fig. 1b are in part based upon the data generated by the TCGA Research Network: http://cancergenome.nih.gov/. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC - IG 18988, IG 23060 to P.P.D.F. and MCO 10.000; IG 18621, IG 22821 and MultiUnit −5 per Mille-22759 to GS; IG 11904, IG 15538, and MCO 10.000 to S.P.); the Italian Ministry of University and Scientific Research (MIUR) to P.P.D.F. (Prot. 2015XS92CC); the Italian Ministry of Health to D.T. (RF-2013-02358446); the Worldwide Cancer Research (16-1245) to S.S.; the European Research Council (Advanced-ERC − 268836) to G.S.; the Cariplo Foundation (2008.2448 to M.V.; 2011-0596 to A.D.). G.G., I.S.L., and C.T. were supported by an AIRC fellowship. This work was also partially supported by the Italian Ministry of Health with Ricerca Corrente and 5 × 1000 funds. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - The subversion of endocytic routes leads to malignant transformation and has been implicated in human cancers. However, there is scarce evidence for genetic alterations of endocytic proteins as causative in high incidence human cancers. Here, we report that Epsin 3 (EPN3) is an oncogene with prognostic and therapeutic relevance in breast cancer. Mechanistically, EPN3 drives breast tumorigenesis by increasing E-cadherin endocytosis, followed by the activation of a β-catenin/TCF4-dependent partial epithelial-to-mesenchymal transition (EMT), followed by the establishment of a TGFβ-dependent autocrine loop that sustains EMT. EPN3-induced partial EMT is instrumental for the transition from in situ to invasive breast carcinoma, and, accordingly, high EPN3 levels are detected at the invasive front of human breast cancers and independently predict metastatic rather than loco-regional recurrence. Thus, we uncover an endocytic-based mechanism able to generate TGFβ-dependent regulatory loops conferring cellular plasticity and invasive behavior.

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