ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
M2-type tumor-associated macrophages promote invasion of canine breast cancer through ADAM9 upregulation
Fangrong Wu
Chae-Yi Kim
Jeong-Woon Lee
Je-Yoel Cho
Seoul National University, Seoul, Republic of Korea
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Abstract
Most cancer progression is strongly influenced by tumor-associated macrophages (TAMs), which represent the most abundant immune cell population in the tumor microenvironment. Here, we identify a consistent enrichment of ADAM9 in M2-polarized TAMs using a canine mammary tumor model, integrated with publicly available human transcriptomic data. Single-cell RNA sequencing further reveals that ADAM9 is expressed in TAMs. Mechanistically, IL-4 induced M2 macrophages not only upregulate ADAM9 but also enhance tumor migration and invasion. Functionally, ADAM9 knockdown attenuates extracellular matrix degradation, reduces MMP9 expression, and disrupts F-actin remodeling. Moreover, cancer stem cell (CSC)–conditioned medium induces ADAM9 expression, indicating that ADAM9 serves as a convergent mediator of CSC–macrophage crosstalk. In spheroid models, ADAM9 depletion further prevents TAM-mediated spheroid destabilization and suppresses collective invasion, underscoring its pivotal role in macrophage-driven tumor progression. Our study thus reveals that ADAM9 is a key effector in TAM driven invasion through ECM remodeling and cytoskeletal regulation, and highlights ADAM9 as a promising therapeutic target in the tumor immune microenvironment.
Summary
Keywords
ADAM9, breast cancer, cancer stem cells, ECM degration, Tumor-associated macrophages
Received
30 December 2025
Accepted
17 February 2026
Copyright
© 2026 Wu, Kim, Lee and Cho. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Je-Yoel Cho
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