CXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis
Abstract Tumor-initiating cells (TICs) share features and regulatory pathways with normal stem cells, yet how the stem cell niche contributes to tumorigenesis remains unclear. Here, we identify CXCR4+ macrophages as a niche population enriched in normal mammary ducts, where they promote the regenera...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59972-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849730940198191104 |
|---|---|
| author | Eunmi Lee Jason J. Hong Gabriel Samcam Vargas Natalie Sauerwald Yong Wei Xiang Hang Chandra L. Theesfeld Jean Arly A. Volmar Jennifer M. Miller Wei Wang Sha Wang Gary Laevsky Christina J. DeCoste Yibin Kang |
| author_facet | Eunmi Lee Jason J. Hong Gabriel Samcam Vargas Natalie Sauerwald Yong Wei Xiang Hang Chandra L. Theesfeld Jean Arly A. Volmar Jennifer M. Miller Wei Wang Sha Wang Gary Laevsky Christina J. DeCoste Yibin Kang |
| author_sort | Eunmi Lee |
| collection | DOAJ |
| description | Abstract Tumor-initiating cells (TICs) share features and regulatory pathways with normal stem cells, yet how the stem cell niche contributes to tumorigenesis remains unclear. Here, we identify CXCR4+ macrophages as a niche population enriched in normal mammary ducts, where they promote the regenerative activity of basal cells in response to luminal cell-derived CXCL12. CXCL12 triggers AKT-mediated stabilization of β-catenin, which induces Wnt ligands and pro-migratory genes, enabling intraductal macrophage infiltration and supporting regenerative activity of basal cells. Notably, these same CXCR4+ niche macrophages regulate the tumor-initiating activity of various breast cancer subtypes by enhancing TIC survival and tumor-forming capacity, while promoting early immune evasion through regulatory T cell induction. Furthermore, a CXCR4+ niche macrophage gene signature correlates with poor prognosis in human breast cancer. These findings highlight the pivotal role of the CXCL12-CXCR4 axis in orchestrating interactions between niche macrophages, mammary epithelial cells, and immune cells, thereby establishing a supportive niche for both normal tissue regeneration and mammary tumor initiation. |
| format | Article |
| id | doaj-art-0badb630b96c45d5b196ead6dedba2f5 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-0badb630b96c45d5b196ead6dedba2f52025-08-20T03:08:43ZengNature PortfolioNature Communications2041-17232025-05-0116112410.1038/s41467-025-59972-zCXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesisEunmi Lee0Jason J. Hong1Gabriel Samcam Vargas2Natalie Sauerwald3Yong Wei4Xiang Hang5Chandra L. Theesfeld6Jean Arly A. Volmar7Jennifer M. Miller8Wei Wang9Sha Wang10Gary Laevsky11Christina J. DeCoste12Yibin Kang13Department of Molecular Biology, Princeton UniversityDepartment of Molecular Biology, Princeton UniversityDepartment of Molecular Biology, Princeton UniversityCenter for Computational Biology, Flatiron InstituteDepartment of Molecular Biology, Princeton UniversityDepartment of Molecular Biology, Princeton UniversityLewis-Sigler Institute for Integrative Genomics, Princeton UniversityLewis-Sigler Institute for Integrative Genomics, Princeton UniversityLewis-Sigler Institute for Integrative Genomics, Princeton UniversityLewis-Sigler Institute for Integrative Genomics, Princeton UniversityDepartment of Molecular Biology, Princeton UniversityDepartment of Molecular Biology, Princeton UniversityDepartment of Molecular Biology, Princeton UniversityDepartment of Molecular Biology, Princeton UniversityAbstract Tumor-initiating cells (TICs) share features and regulatory pathways with normal stem cells, yet how the stem cell niche contributes to tumorigenesis remains unclear. Here, we identify CXCR4+ macrophages as a niche population enriched in normal mammary ducts, where they promote the regenerative activity of basal cells in response to luminal cell-derived CXCL12. CXCL12 triggers AKT-mediated stabilization of β-catenin, which induces Wnt ligands and pro-migratory genes, enabling intraductal macrophage infiltration and supporting regenerative activity of basal cells. Notably, these same CXCR4+ niche macrophages regulate the tumor-initiating activity of various breast cancer subtypes by enhancing TIC survival and tumor-forming capacity, while promoting early immune evasion through regulatory T cell induction. Furthermore, a CXCR4+ niche macrophage gene signature correlates with poor prognosis in human breast cancer. These findings highlight the pivotal role of the CXCL12-CXCR4 axis in orchestrating interactions between niche macrophages, mammary epithelial cells, and immune cells, thereby establishing a supportive niche for both normal tissue regeneration and mammary tumor initiation.https://doi.org/10.1038/s41467-025-59972-z |
| spellingShingle | Eunmi Lee Jason J. Hong Gabriel Samcam Vargas Natalie Sauerwald Yong Wei Xiang Hang Chandra L. Theesfeld Jean Arly A. Volmar Jennifer M. Miller Wei Wang Sha Wang Gary Laevsky Christina J. DeCoste Yibin Kang CXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis Nature Communications |
| title | CXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis |
| title_full | CXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis |
| title_fullStr | CXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis |
| title_full_unstemmed | CXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis |
| title_short | CXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis |
| title_sort | cxcr4 mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis |
| url | https://doi.org/10.1038/s41467-025-59972-z |
| work_keys_str_mv | AT eunmilee cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT jasonjhong cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT gabrielsamcamvargas cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT nataliesauerwald cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT yongwei cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT xianghang cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT chandraltheesfeld cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT jeanarlyavolmar cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT jennifermmiller cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT weiwang cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT shawang cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT garylaevsky cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT christinajdecoste cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis AT yibinkang cxcr4mammaryglandmacrophagealnichepromotestumorinitiatingcellactivityandimmunesuppressionduringtumorigenesis |