COX2 contributes to the spatial reorganization of B7H4+ and CD44v6+ niches promoting therapy resistance in ER- breast cancer
Abstract Estrogen receptor-negative (ER-) breast tumors are aggressive subtypes with limited therapeutic options. Cyclooxygenase-2 promotes chronic inflammation, immune suppression, and therapeutic resistance. Whether COX2 signaling organizes tumor microenvironments across oxygen gradients remains unclear. Restricted Exchange Environment Chambers (REECs) were used to explore the COX2 impact on spatial tumor architecture across oxygen gradients. Baseline COX2+, B7H4+, and CD44v6+ cells exhibited distinct distributions, with CD44v6 predominance. Inflammatory stimulation increased and spatially reorganized COX2+, B7H4+, and COX2+CD44v6+ populations. While COX2+ cells occupied oxygenated-to-intermediate zones, B7H4+ populations were enriched in intermediate-to-hypoxic regions, and CD44v6 remained broadly distributed. Diclofenac disrupted this organization and reduced clustering of COX2+, B7H4+, and COX2+CD44v6+ phenotypes. Poor-outcome patients showed high COX2 at the tumor-stroma interface as well as altered COX2+, B7H4+, and CD44v6+ clustering phenotypes. These findings identify COX2-dependent microenvironments as clinically relevant features of therapeutic resistance. Diclofenac preferentially depleted hypoxic compartments preserved following cisplatin treatment alone, supporting the targeting of spatially organized inflammatory niches to improve therapeutic response.
Authors
- Lisa A. Ridnour (ORCID: https://orcid.org/0000-0001-9446-8349)
- Stephen Lockett (ORCID: https://orcid.org/0000-0002-2010-9914)
- Erika Mariana Palmieri (ORCID: https://orcid.org/0000-0002-4237-5324)
- Sharon Anneve Glynn (ORCID: https://orcid.org/0000-0003-1459-2580)
- Jenny C. Chang (ORCID: https://orcid.org/0000-0002-0890-9302)
- David A. Wink (ORCID: https://orcid.org/0000-0002-5652-7480)
- William F. Heinz (ORCID: https://orcid.org/0000-0002-6194-0536)
- Ana L. Gonzalez (ORCID: https://orcid.org/0009-0003-9125-3758)
- Robert Y.S. Cheng (ORCID: https://orcid.org/0000-0003-0287-6439)
- Timothy R. Billiar (ORCID: https://orcid.org/0000-0002-2949-0811)
- Stanley Lipkowitz (ORCID: https://orcid.org/0000-0002-6103-2255)
- Elijah F. Edmondson (ORCID: https://orcid.org/0000-0002-6106-3705)
- Daniel W. McVicar (ORCID: https://orcid.org/0000-0002-1112-5111)
- Leandro L. Coutinho (ORCID: https://orcid.org/0000-0002-0989-6144)
- Stephen K. Anderson (ORCID: https://orcid.org/0000-0002-7856-4266)
- Donna O. Butcher (ORCID: https://orcid.org/0000-0002-2065-8067)
- Rebecca L. Moffat (ORCID: https://orcid.org/0009-0000-2675-8707)
- Stephen T. C. Wong (ORCID: https://orcid.org/0000-0001-9188-6502)
- M.Cristina Rangel
- Milind Pore
- Xiaoxian Li
Institutions
- Houston Methodist (US)
- National Institutes of Health (US)
- Emory University (US)
- Universidade de São Paulo (BR)
- Ollscoil na Gaillimhe – University of Galway (IE)
- Instituto do Câncer do Estado de São Paulo (BR)
- Frederick National Laboratory for Cancer Research (US)
- University of Pittsburgh Medical Center (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
Publication Details
- Journal
- Communications Biology
- Published
- 2026-11-02
- DOI
- https://doi.org/10.1038/s42003-026-11285-7
- Primary Topic
- Inflammatory mediators and NSAID effects
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Cancer Institute