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Background: The inherent plasticity of tumor cells provides a mechanism of resistance to molecularly targeted therapies, exemplified by adeno-to-neuroendocrine lineage transitions in prostate and lung cancer. Here we investigate the root cause of lineage plasticity following Trp53 and Rb1 loss in genetically engineered mouse models, murine and patient-derived organoid cultures, and patient biospecimens with castrate-resistant prostate cancer.

Materials and methods: We performed single-cell transcriptomic analysis in time-course experiments in murine prostate organoids and genetically engineered mouse models following Trp53 and Rb1 deletion. We conducted additional single-cell profiling in an independent cohort of patients with metastatic castrate-resistant prostate cancer. Genetic and pharmacological studies in murine and patient-derived organoids served as functional validation.

Results: In time-course …