Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages

Ilaria Marigo; Rosalinda Trovato; Francesca Hofer; Vincenzo Ingangi; Giacomo Desantis; Kevin Leone; Francesco De Sanctis; Stefano Ugel; Stefania Canè; Anna Simonelli; Alessia Lamolinara; Manuela Iezzi; Matteo Fassan; Massimo Rugge; Federico Boschi; Giulia Borile; Thomas Eisenhaure; Siranush Sarkizova; David Lieb; Nir Hacohen; Luca Azzolin; Stefano Piccolo; Rita Lawlor; Aldo Scarpa; Luisa Carbognin; Emilio Bria; Silvio Bicciato; Peter J Murray; Vincenzo Bronte

doi:10.1158/2159-8290.CD-20-0036

Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages

Ilaria Marigo, Rosalinda Trovato, Francesca Hofer, Vincenzo Ingangi, Giacomo Desantis, Kevin Leone, Francesco De Sanctis, Stefano Ugel, Stefania Canè, Anna Simonelli, Alessia Lamolinara, Manuela Iezzi, Matteo Fassan, Massimo Rugge, Federico Boschi, Giulia Borile, Thomas Eisenhaure, Siranush Sarkizova, David Lieb, Nir HacohenLuca Azzolin, Stefano Piccolo, Rita Lawlor, Aldo Scarpa, Luisa Carbognin, Emilio Bria, Silvio Bicciato, Peter J Murray, Vincenzo Bronte

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

Abstract

Tumor-associated macrophages (TAM) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and that its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor-invasive front, participate in integrin recycling, ECM remodeling, and directional migration in a tridimensional matrix. DAB2+ macrophages escort the invasive dissemination of cancer cells by a mechanosensing pathway requiring the transcription factor YAP. In human lobular breast and gastric carcinomas, DAB2+ TAMs correlated with a poor clinical outcome, identifying DAB2 as potential prognostic biomarker for stratification of patients with cancer. DAB2 is therefore central for the prometastatic activity of TAMs. SIGNIFICANCE: DAB2 expression in macrophages is essential for metastasis formation but not primary tumor growth. Mechanosensing cues, activating the complex YAP-TAZ, regulate DAB2 in macrophages, which in turn controls integrin recycling and ECM remodeling in 3-D tissue matrix. The presence of DAB2+ TAMs in patients with cancer correlates with worse prognosis.This article is highlighted in the In This Issue feature, p. 1611.

Original language	English
Pages (from-to)	1758-1773
Number of pages	16
Journal	Cancer Discovery
Volume	10
Issue number	11
DOIs	https://doi.org/10.1158/2159-8290.CD-20-0036
Publication status	Published - Nov 2020

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Marigo, I., Trovato, R., Hofer, F., Ingangi, V., Desantis, G., Leone, K., De Sanctis, F., Ugel, S., Canè, S., Simonelli, A., Lamolinara, A., Iezzi, M., Fassan, M., Rugge, M., Boschi, F., Borile, G., Eisenhaure, T., Sarkizova, S., Lieb, D., ... Bronte, V. (2020). Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages. Cancer Discovery, 10(11), 1758-1773. https://doi.org/10.1158/2159-8290.CD-20-0036

Marigo, I, Trovato, R, Hofer, F, Ingangi, V, Desantis, G, Leone, K, De Sanctis, F, Ugel, S, Canè, S, Simonelli, A, Lamolinara, A, Iezzi, M, Fassan, M, Rugge, M, Boschi, F, Borile, G, Eisenhaure, T, Sarkizova, S, Lieb, D, Hacohen, N, Azzolin, L, Piccolo, S, Lawlor, R, Scarpa, A, Carbognin, L, Bria, E, Bicciato, S, Murray, PJ & Bronte, V 2020, 'Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages', Cancer Discovery, vol. 10, no. 11, pp. 1758-1773. https://doi.org/10.1158/2159-8290.CD-20-0036

@article{ca0c94497858462291324abe8dc7627f,

title = "Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages",

abstract = "Tumor-associated macrophages (TAM) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and that its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor-invasive front, participate in integrin recycling, ECM remodeling, and directional migration in a tridimensional matrix. DAB2+ macrophages escort the invasive dissemination of cancer cells by a mechanosensing pathway requiring the transcription factor YAP. In human lobular breast and gastric carcinomas, DAB2+ TAMs correlated with a poor clinical outcome, identifying DAB2 as potential prognostic biomarker for stratification of patients with cancer. DAB2 is therefore central for the prometastatic activity of TAMs. SIGNIFICANCE: DAB2 expression in macrophages is essential for metastasis formation but not primary tumor growth. Mechanosensing cues, activating the complex YAP-TAZ, regulate DAB2 in macrophages, which in turn controls integrin recycling and ECM remodeling in 3-D tissue matrix. The presence of DAB2+ TAMs in patients with cancer correlates with worse prognosis.This article is highlighted in the In This Issue feature, p. 1611.",

author = "Ilaria Marigo and Rosalinda Trovato and Francesca Hofer and Vincenzo Ingangi and Giacomo Desantis and Kevin Leone and {De Sanctis}, Francesco and Stefano Ugel and Stefania Can{\`e} and Anna Simonelli and Alessia Lamolinara and Manuela Iezzi and Matteo Fassan and Massimo Rugge and Federico Boschi and Giulia Borile and Thomas Eisenhaure and Siranush Sarkizova and David Lieb and Nir Hacohen and Luca Azzolin and Stefano Piccolo and Rita Lawlor and Aldo Scarpa and Luisa Carbognin and Emilio Bria and Silvio Bicciato and Murray, {Peter J} and Vincenzo Bronte",

note = "{\textcopyright}2020 American Association for Cancer Research.",

year = "2020",

month = nov,

doi = "10.1158/2159-8290.CD-20-0036",

language = "English",

volume = "10",

pages = "1758--1773",

journal = "Cancer Discovery",

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T1 - Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages

AU - Marigo, Ilaria

AU - Trovato, Rosalinda

AU - Hofer, Francesca

AU - Ingangi, Vincenzo

AU - Desantis, Giacomo

AU - Leone, Kevin

AU - De Sanctis, Francesco

AU - Ugel, Stefano

AU - Canè, Stefania

AU - Simonelli, Anna

AU - Lamolinara, Alessia

AU - Iezzi, Manuela

AU - Fassan, Matteo

AU - Rugge, Massimo

AU - Boschi, Federico

AU - Borile, Giulia

AU - Eisenhaure, Thomas

AU - Sarkizova, Siranush

AU - Lieb, David

AU - Hacohen, Nir

AU - Azzolin, Luca

AU - Piccolo, Stefano

AU - Lawlor, Rita

AU - Scarpa, Aldo

AU - Carbognin, Luisa

AU - Bria, Emilio

AU - Bicciato, Silvio

AU - Murray, Peter J

AU - Bronte, Vincenzo

PY - 2020/11

Y1 - 2020/11

N2 - Tumor-associated macrophages (TAM) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and that its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor-invasive front, participate in integrin recycling, ECM remodeling, and directional migration in a tridimensional matrix. DAB2+ macrophages escort the invasive dissemination of cancer cells by a mechanosensing pathway requiring the transcription factor YAP. In human lobular breast and gastric carcinomas, DAB2+ TAMs correlated with a poor clinical outcome, identifying DAB2 as potential prognostic biomarker for stratification of patients with cancer. DAB2 is therefore central for the prometastatic activity of TAMs. SIGNIFICANCE: DAB2 expression in macrophages is essential for metastasis formation but not primary tumor growth. Mechanosensing cues, activating the complex YAP-TAZ, regulate DAB2 in macrophages, which in turn controls integrin recycling and ECM remodeling in 3-D tissue matrix. The presence of DAB2+ TAMs in patients with cancer correlates with worse prognosis.This article is highlighted in the In This Issue feature, p. 1611.

AB - Tumor-associated macrophages (TAM) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and that its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor-invasive front, participate in integrin recycling, ECM remodeling, and directional migration in a tridimensional matrix. DAB2+ macrophages escort the invasive dissemination of cancer cells by a mechanosensing pathway requiring the transcription factor YAP. In human lobular breast and gastric carcinomas, DAB2+ TAMs correlated with a poor clinical outcome, identifying DAB2 as potential prognostic biomarker for stratification of patients with cancer. DAB2 is therefore central for the prometastatic activity of TAMs. SIGNIFICANCE: DAB2 expression in macrophages is essential for metastasis formation but not primary tumor growth. Mechanosensing cues, activating the complex YAP-TAZ, regulate DAB2 in macrophages, which in turn controls integrin recycling and ECM remodeling in 3-D tissue matrix. The presence of DAB2+ TAMs in patients with cancer correlates with worse prognosis.This article is highlighted in the In This Issue feature, p. 1611.

U2 - 10.1158/2159-8290.CD-20-0036

DO - 10.1158/2159-8290.CD-20-0036

M3 - Article

C2 - 32651166

VL - 10

SP - 1758

EP - 1773

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 11

ER -

Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages

Abstract

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