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Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis

Macrophage infiltration in mammary tumors is associated with enhanced tumor progression, metastasis, and poor clinical outcome, and considered as target for therapeutic intervention. By using different genetic mouse models, the authors show that ablation of the tyrosine kinase PYK2, either in breast...

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Autores principales: Müller, Anna‐Katharina, Köhler, Ulrike A., Trzebanski, Sébastien, Vinik, Yaron, Raj, Harsha Mohan, Girault, Jean‐Antoine, Ben‐Chetrit, Nir, Maraver, Antonio, Jung, Steffen, Lev, Sima
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948556/
https://www.ncbi.nlm.nih.gov/pubmed/35092356
http://dx.doi.org/10.1002/advs.202105696
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author Müller, Anna‐Katharina
Köhler, Ulrike A.
Trzebanski, Sébastien
Vinik, Yaron
Raj, Harsha Mohan
Girault, Jean‐Antoine
Ben‐Chetrit, Nir
Maraver, Antonio
Jung, Steffen
Lev, Sima
author_facet Müller, Anna‐Katharina
Köhler, Ulrike A.
Trzebanski, Sébastien
Vinik, Yaron
Raj, Harsha Mohan
Girault, Jean‐Antoine
Ben‐Chetrit, Nir
Maraver, Antonio
Jung, Steffen
Lev, Sima
author_sort Müller, Anna‐Katharina
collection PubMed
description Macrophage infiltration in mammary tumors is associated with enhanced tumor progression, metastasis, and poor clinical outcome, and considered as target for therapeutic intervention. By using different genetic mouse models, the authors show that ablation of the tyrosine kinase PYK2, either in breast cancer cells, only in the tumor microenvironment, or in both, markedly reduces the number of infiltrating tumor macrophages and concomitantly inhibits tumor angiogenesis and tumor growth. Strikingly, PYK2 ablation only in macrophages is sufficient to induce similar effects. These phenotypic changes are associated with reduced monocyte recruitment and a substantial decrease in tumor‐associated macrophages (TAMs). Mechanistically, the authors show that PYK2 mediates mutual communication between breast cancer cells and macrophages through critical effects on key receptor signaling. Specifically, PYK2 ablation inhibits Notch1 signaling and consequently reduces CCL2 secretion by breast cancer cells, and concurrently reduces the levels of CCR2, CXCR4, IL‐4Rα, and Stat6 activation in macrophages. These bidirectional effects modulate monocyte recruitment, macrophage polarization, and tumor angiogenesis. The expression of PYK2 is correlated with infiltrated macrophages in breast cancer patients, and its effects on macrophage infiltration and pro‐tumorigenic phenotype suggest that PYK2 targeting can be utilized as an effective strategy to modulate TAMs and possibly sensitize breast cancer to immunotherapy.
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spelling pubmed-89485562022-03-29 Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis Müller, Anna‐Katharina Köhler, Ulrike A. Trzebanski, Sébastien Vinik, Yaron Raj, Harsha Mohan Girault, Jean‐Antoine Ben‐Chetrit, Nir Maraver, Antonio Jung, Steffen Lev, Sima Adv Sci (Weinh) Research Articles Macrophage infiltration in mammary tumors is associated with enhanced tumor progression, metastasis, and poor clinical outcome, and considered as target for therapeutic intervention. By using different genetic mouse models, the authors show that ablation of the tyrosine kinase PYK2, either in breast cancer cells, only in the tumor microenvironment, or in both, markedly reduces the number of infiltrating tumor macrophages and concomitantly inhibits tumor angiogenesis and tumor growth. Strikingly, PYK2 ablation only in macrophages is sufficient to induce similar effects. These phenotypic changes are associated with reduced monocyte recruitment and a substantial decrease in tumor‐associated macrophages (TAMs). Mechanistically, the authors show that PYK2 mediates mutual communication between breast cancer cells and macrophages through critical effects on key receptor signaling. Specifically, PYK2 ablation inhibits Notch1 signaling and consequently reduces CCL2 secretion by breast cancer cells, and concurrently reduces the levels of CCR2, CXCR4, IL‐4Rα, and Stat6 activation in macrophages. These bidirectional effects modulate monocyte recruitment, macrophage polarization, and tumor angiogenesis. The expression of PYK2 is correlated with infiltrated macrophages in breast cancer patients, and its effects on macrophage infiltration and pro‐tumorigenic phenotype suggest that PYK2 targeting can be utilized as an effective strategy to modulate TAMs and possibly sensitize breast cancer to immunotherapy. John Wiley and Sons Inc. 2022-01-29 /pmc/articles/PMC8948556/ /pubmed/35092356 http://dx.doi.org/10.1002/advs.202105696 Text en © 2022 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Müller, Anna‐Katharina
Köhler, Ulrike A.
Trzebanski, Sébastien
Vinik, Yaron
Raj, Harsha Mohan
Girault, Jean‐Antoine
Ben‐Chetrit, Nir
Maraver, Antonio
Jung, Steffen
Lev, Sima
Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis
title Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis
title_full Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis
title_fullStr Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis
title_full_unstemmed Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis
title_short Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis
title_sort mouse modeling dissecting macrophage–breast cancer communication uncovered roles of pyk2 in macrophage recruitment and breast tumorigenesis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948556/
https://www.ncbi.nlm.nih.gov/pubmed/35092356
http://dx.doi.org/10.1002/advs.202105696
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