EYA3 regulation of NF-κB and CCL2 suppresses cytotoxic NK cells in the premetastatic niche to promote TNBC metastasis

Sheera R. Rosenbaum; Connor J. Hughes; Kaiah M. Fields; Stephen Connor Purdy; Annika L. Gustafson; Arthur Wolin; Drake Hampton; Natasha M. Shrivastava; Nicholas Turner; Etienne Danis; Christopher Ebmeier; Nicole Spoelstra; Jennifer Richer; Paul Jedlicka; James C. Costello; Rui Zhao; Heide L. Ford

doi:10.1126/sciadv.adt0504

EYA3 regulation of NF-κB and CCL2 suppresses cytotoxic NK cells in the premetastatic niche to promote TNBC metastasis

Sheera R. Rosenbaum, Connor J. Hughes, Kaiah M. Fields, Stephen Connor Purdy, Annika L. Gustafson, Arthur Wolin, Drake Hampton, Natasha M. Shrivastava, Nicholas Turner, Etienne Danis, Christopher Ebmeier, Nicole Spoelstra, Jennifer Richer, Paul Jedlicka, James C. Costello, Rui Zhao, Heide L. Ford

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Abstract

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.

Original language	English
Article number	eadt0504
Journal	Science Advances
Volume	11
Issue number	19
DOIs	https://doi.org/10.1126/sciadv.adt0504
State	Published - May 9 2025

Funding

Special thanks to S. Ferrara for assistance with RNA-seq data processing. Thank you to P. Ernst, PhD, for subcloning and providing aliquots of the pLVX-EF1a-IRESmCherry empty vector and IKK2-SE plasmids. We thank the Human Immune Monitoring Shared Resource (RRID:SCR_021985) within the University of Colorado Human Immunology and Immunotherapy Initiative and the University of Colorado Cancer Center (P30CA046934) for expert assistance in analysis of Vectra staining. This work also used the Cell Technologies (RRID:SCR_021982), Genomics (RRID:SCR_021984), Biostatistics and Bioinformatics (RRID:SCR_021982), and Flow Cytometry (RRID:SCR_022035) shared resources at the University of Colorado Anschutz Medical Campus and the University of Colorado Cancer Center (P30CA046934). This work was supported by National Institutes of Health grants R01CA224867 (H.L.F.), R01CA221282 (H.L.F. and R.Z.), R01CA301267 (H.L.F. and R.Z.), R01CA275187 (H.L.F.), K00CA245552 (S.R.R.), F30CA257215 (C.J.H.), F31CA275314 (A.W.), and P30CA046934 (shared resources at the University of Colorado Cancer Center).

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Rosenbaum, S. R., Hughes, C. J., Fields, K. M., Purdy, S. C., Gustafson, A. L., Wolin, A., Hampton, D., Shrivastava, N. M., Turner, N., Danis, E., Ebmeier, C., Spoelstra, N., Richer, J., Jedlicka, P., Costello, J. C., Zhao, R., & Ford, H. L. (2025). EYA3 regulation of NF-κB and CCL2 suppresses cytotoxic NK cells in the premetastatic niche to promote TNBC metastasis. Science Advances, 11(19), Article eadt0504. https://doi.org/10.1126/sciadv.adt0504

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title = "EYA3 regulation of NF-κB and CCL2 suppresses cytotoxic NK cells in the premetastatic niche to promote TNBC metastasis",

abstract = "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.",

author = "Rosenbaum, {Sheera R.} and Hughes, {Connor J.} and Fields, {Kaiah M.} and Purdy, {Stephen Connor} and Gustafson, {Annika L.} and Arthur Wolin and Drake Hampton and Shrivastava, {Natasha M.} and Nicholas Turner and Etienne Danis and Christopher Ebmeier and Nicole Spoelstra and Jennifer Richer and Paul Jedlicka and Costello, {James C.} and Rui Zhao and Ford, {Heide L.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 The Authors, some rights reserved.",

year = "2025",

month = may,

day = "9",

doi = "10.1126/sciadv.adt0504",

language = "English",

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Rosenbaum, SR, Hughes, CJ, Fields, KM, Purdy, SC, Gustafson, AL, Wolin, A, Hampton, D, Shrivastava, NM, Turner, N, Danis, E, Ebmeier, C, Spoelstra, N, Richer, J, Jedlicka, P, Costello, JC, Zhao, R & Ford, HL 2025, 'EYA3 regulation of NF-κB and CCL2 suppresses cytotoxic NK cells in the premetastatic niche to promote TNBC metastasis', Science Advances, vol. 11, no. 19, eadt0504. https://doi.org/10.1126/sciadv.adt0504

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T1 - EYA3 regulation of NF-κB and CCL2 suppresses cytotoxic NK cells in the premetastatic niche to promote TNBC metastasis

AU - Rosenbaum, Sheera R.

AU - Hughes, Connor J.

AU - Fields, Kaiah M.

AU - Purdy, Stephen Connor

AU - Gustafson, Annika L.

AU - Wolin, Arthur

AU - Hampton, Drake

AU - Shrivastava, Natasha M.

AU - Turner, Nicholas

AU - Danis, Etienne

AU - Ebmeier, Christopher

AU - Spoelstra, Nicole

AU - Richer, Jennifer

AU - Jedlicka, Paul

AU - Costello, James C.

AU - Zhao, Rui

AU - Ford, Heide L.

PY - 2025/5/9

Y1 - 2025/5/9

N2 - 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.

AB - 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.

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EYA3 regulation of NF-κB and CCL2 suppresses cytotoxic NK cells in the premetastatic niche to promote TNBC metastasis

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