Up to 40% of patients with estrogen receptor positive breast cancer will experience relapse, either while on endocrine therapy (ET) or after ET is completed. A major contributor to ET failure is the presence of ET-insensitive cell populations within tumors. Here, we developed an analytical pipeline to systematically identify and target these populations by integrating single-cell RNA sequencing of ER+ tumors from the FELINE clinical trial with functional validation in a panel of patient-derived xenograft organoid models. We found that ET-insensitive cells are detected in all tumors regardless of clinical response and exhibit higher transcriptional heterogeneity than ET-sensitive populations. Using our pipeline, we identified and validated new therapeutic options that target patient-specific and shared ET-insensitive populations. Our integrated workflow provides a robust platform for identifying and targeting ET-insensitive cells and offers a translational framework to develop precision medicine approaches to improve outcome in breast cancer patients.
Semina, S., Huggins, R. J., Zhao, H., Yanagihara, K., Sheinin, M., Macias, V., Alani, F., Feferman, L., Kajdacsy-Balla, A. A., Tonetti, D., Hoskins, K., Frasor, J., Coloff, J. L.
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