Spatial context of cellular heterogeneity in triple-negative breast cancer reveals actionable subtypes
- 1UC San Diego
Abstract
Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous disease with limited targeted treatment options. Leveraging bulk and spatial transcriptomics and cellular mapping of breast tissue from a large patient cohort, we identified three reproducible TNBC ecosystem subtypes that encode distinct spatial tumor-microenvironment architectures and clinically relevant treatment-response phenotype. Our analyses define: (1) an immune-exhausted subtype associated with immune checkpoint therapy (ICT); (2) a highly fibrotic/hypoxic subtype; and (3) a metabolically reprogrammed subtype characterized by nuclear-receptor and fatty-acid signaling. Spatial profiling further revealed subtype-specific organization of epithelial, immune, and stromal programs across tumor centers and invasive edges. Multiplexed imaging independently supported the contrasting immune-infiltrated and stromal-excluded architectures of the immune-engaged and fibrotic subtypes. The unique markers associated with the subtypes also provide the basis for subtyping and candidate therapeutic vulnerabilities. Our study provides a robust framework for personalized medicine, highlighting that targeting specific spatio-cellular architectures is critical to improving clinical outcomes.
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BibTeX
@misc{mesrizadeh2026spatial,
title = {{Spatial context of cellular heterogeneity in triple-negative breast cancer reveals actionable subtypes}},
author = {Z. Mesrizadeh and K. Mukund and L. Yang and R. K. Pillai and D. E. Frankhouser and D. Schmolze and S. L. Neuhausen and J. Zabaleta and L. D. Valle and J. Tomsic and Y. C. Ding and A. Ochoa and L. Miele and V. Seewaldt and S. Subramaniam},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.10.758236},
url = {https://www.biorxiv.org/content/10.64898/2026.10.10.758236v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Spatial context of cellular heterogeneity in triple-negative breast cancer reveals actionable subtypes
AU - Z. Mesrizadeh
AU - K. Mukund
AU - L. Yang
AU - R. K. Pillai
AU - D. E. Frankhouser
AU - D. Schmolze
AU - S. L. Neuhausen
AU - J. Zabaleta
AU - L. D. Valle
AU - J. Tomsic
AU - Y. C. Ding
AU - A. Ochoa
AU - L. Miele
AU - V. Seewaldt
AU - S. Subramaniam
PY - 2026
DA - 2026/10/10
PB - bioRxiv
DO - 10.64898/2026.10.10.758236
UR - https://www.biorxiv.org/content/10.64898/2026.10.10.758236v1
AB - Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous disease with limited targeted treatment options. Leveraging bulk and spatial transcriptomics and cellular mapping of breast tissue from a large patient cohort, we identified three reproducible TNBC ecosystem subtypes that encode distinct spatial tumor-microenvironment architectures and clinically relevant treatment-response phenotype. Our analyses define: (1) an immune-exhausted subtype associated with immune checkpoint therapy (ICT); (2) a highly fibrotic/hypoxic subtype; and (3) a metabolically reprogrammed subtype characterized by nuclear-receptor and fatty-acid signaling. Spatial profiling further revealed subtype-specific organization of epithelial, immune, and stromal programs across tumor centers and invasive edges. Multiplexed imaging independently supported the contrasting immune-infiltrated and stromal-excluded architectures of the immune-engaged and fibrotic subtypes. The unique markers associated with the subtypes also provide the basis for subtyping and candidate therapeutic vulnerabilities. Our study provides a robust framework for personalized medicine, highlighting that targeting specific spatio-cellular architectures is critical to improving clinical outcomes.
ER -