Cyclic Hypoxia drives Wnt5a-ROR1 stroma-tumor crosstalk promoting breast cancer growth
- 1University of Connecticut Health
Abstract
Tumor hypoxia can be stable, or cyclic based on proximity to vasculature, and affects not just the cancer cells, but also other cells in the tumor microenvironment (TME). Although cyclic hypoxia can affect cells in the tumor microenvironment differently from stable hypoxia, its effect on non-malignant cells in the tumor microenvironment (TME) is unclear. Here, using single cell RNA ATAC sequencing of multicellular co-culture model of triple-negative breast cancer (TNBC), comprising MDA-MB-231 cells, fibroblasts (Fbs), mesenchymal stromal cells (MSCs), endothelial cells, and macrophages, we systemically map the transcriptomic response shaped by dynamic oxygen regimes. Cyclic hypoxia induced a distinct transcriptional program compared to stable hypoxia in a cell type specific manner, regulating cell subpopulation proportions with key phenotypic implications. In TNBC, cyclic hypoxia reversed chronic hypoxia-induced cell cycle arrest, and reversed the enrichment of a highly mesenchymal WNT5A+/COL6+ subpopulation stabilized in hypoxia. Furthermore, cyclic hypoxia increased fibroblast activation, but suppressed MSC proliferation. Mechanistically, cyclic hypoxia coordinated paracrine WNT5A/B-ROR1 signaling between fibroblasts and TNBCs. In a mouse breast CAF-TNBC co-xenograft model, disrupting this cyclic hypoxia driven WNT5A-ROR1 stroma-cancer crosstalk reduced tumor growth in vivo. Together, our findings highlight dynamics in oxygen regimen as distinct microenvironmental cues, reprograming the TME compartments to accelerate cancer growth and invasion.
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BibTeX
@misc{liu2026cyclic,
title = {{Cyclic Hypoxia drives Wnt5a-ROR1 stroma-tumor crosstalk promoting breast cancer growth}},
author = {Y. Liu and S. Liu and S. Sahoo and X. Wang and W. Du and D. D. Ellison and J. Afzal and Y. Suhail and M. K. Jolly and Kshitiz},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.11.758391},
url = {https://www.biorxiv.org/content/10.64898/2026.10.11.758391v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cyclic Hypoxia drives Wnt5a-ROR1 stroma-tumor crosstalk promoting breast cancer growth
AU - Y. Liu
AU - S. Liu
AU - S. Sahoo
AU - X. Wang
AU - W. Du
AU - D. D. Ellison
AU - J. Afzal
AU - Y. Suhail
AU - M. K. Jolly
AU - Kshitiz
PY - 2026
DA - 2026/10/11
PB - bioRxiv
DO - 10.64898/2026.10.11.758391
UR - https://www.biorxiv.org/content/10.64898/2026.10.11.758391v1
AB - Tumor hypoxia can be stable, or cyclic based on proximity to vasculature, and affects not just the cancer cells, but also other cells in the tumor microenvironment (TME). Although cyclic hypoxia can affect cells in the tumor microenvironment differently from stable hypoxia, its effect on non-malignant cells in the tumor microenvironment (TME) is unclear. Here, using single cell RNA ATAC sequencing of multicellular co-culture model of triple-negative breast cancer (TNBC), comprising MDA-MB-231 cells, fibroblasts (Fbs), mesenchymal stromal cells (MSCs), endothelial cells, and macrophages, we systemically map the transcriptomic response shaped by dynamic oxygen regimes. Cyclic hypoxia induced a distinct transcriptional program compared to stable hypoxia in a cell type specific manner, regulating cell subpopulation proportions with key phenotypic implications. In TNBC, cyclic hypoxia reversed chronic hypoxia-induced cell cycle arrest, and reversed the enrichment of a highly mesenchymal WNT5A+/COL6+ subpopulation stabilized in hypoxia. Furthermore, cyclic hypoxia increased fibroblast activation, but suppressed MSC proliferation. Mechanistically, cyclic hypoxia coordinated paracrine WNT5A/B-ROR1 signaling between fibroblasts and TNBCs. In a mouse breast CAF-TNBC co-xenograft model, disrupting this cyclic hypoxia driven WNT5A-ROR1 stroma-cancer crosstalk reduced tumor growth in vivo. Together, our findings highlight dynamics in oxygen regimen as distinct microenvironmental cues, reprograming the TME compartments to accelerate cancer growth and invasion.
ER -