EYA3 regulation of NF-κB and CCL2 suppresses cytotoxic NK cells in the premetastatic niche to promote TNBC metastasis
Triple-negative breast cancer cells must evade immune surveillance to metastasize to distant sites, yet this process is not well understood. The Eyes absent (EYA) family of proteins, which are crucial for embryonic development, become dysregulated in cancer, where they have been shown to mediate proliferation, migration, and invasion. Our study reveals an unusual mechanism by which EYA3 reduces the presence of cytotoxic natural killer (NK) cells in the premetastatic niche (PMN) to enhance metastasis, independent of its effects on the primary tumor. We find that EYA3 up-regulates nuclear factor κB signaling to enhance CCL2 expression, which, in contrast to previous findings, suppresses cytotoxic NK cell activation in vitro and their infiltration into the PMN in vivo. These findings uncover an unexpected role for CCL2 in inhibiting NK cell responses at the PMN and suggest that targeting EYA3 could be an effective strategy to reactivate antitumor immune responses to inhibit metastasis.
Authors
- Heide L. Ford (ORCID: https://orcid.org/0000-0002-2860-9841)
- Jennifer K. Richer (ORCID: https://orcid.org/0000-0002-9960-0991)
- Arthur Wolin (ORCID: https://orcid.org/0000-0003-1881-390X)
- Annika Gustafson (ORCID: https://orcid.org/0000-0002-3796-1222)
- James C. Costello (ORCID: https://orcid.org/0000-0003-3158-9682)
- Etienne Danis (ORCID: https://orcid.org/0000-0002-5651-8111)
- Connor J. Hughes (ORCID: https://orcid.org/0000-0001-6295-8167)
- Christopher C. Ebmeier (ORCID: https://orcid.org/0000-0001-7940-6190)
- Kaiah M. Fields (ORCID: https://orcid.org/0000-0002-7701-7009)
- Nicole S. Spoelstra (ORCID: https://orcid.org/0009-0003-3981-5960)
- Natasha Shrivastava
- Sheera R. Rosenbaum (ORCID: https://orcid.org/0000-0002-7917-2969)
- Nicholas Turner (ORCID: https://orcid.org/0000-0003-0650-4894)
- Rui Zhao (ORCID: https://orcid.org/0000-0003-0045-2974)
- Paul Jedlicka (ORCID: https://orcid.org/0000-0001-7839-6912)
- Stephen C. Purdy (ORCID: https://orcid.org/0000-0001-9640-5501)
- Drake Hampton
Institutions
- University of Colorado Boulder (US)
- University of Colorado Cancer Center (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-05-07
- DOI
- https://doi.org/10.1126/sciadv.adt0504
- Citations
- 5
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 3.99