| Accession | PRJCA011963 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Title | Foxa2 drives lineage plasticity and Kit pathway activation in neuroendocrine prostate cancer | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Relevance | Medical | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Data types |
Epigenomics
Transcriptome or Gene expression Single cell sequencing |
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| Organisms | Mus musculus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | Prostate cancer adeno-to-neuroendocrine lineage transition has emerged as a mechanism of targeted therapeutic resistance. Identifying the direct molecular drivers and developing pharmacological strategies using clinical-grade inhibitors to overcome current lineage transition-induced therapeutic resistance are imperative. Here, using single-cell multiomics analyses, we investigated the dynamics of cellular heterogeneity, transcriptomics regulation and microenvironmental factors in 107,201 cells from mouse prostate cancer samples with complete time series of tumor evolution seen in patients. We identified Foxa2 orchestrated prostate cancer adeno-to-neuroendocrine lineage transition, and Foxa2 expression was significantly induced by androgen deprivation. Moreover, Foxa2 knockdown induced the reversal of adeno-to-neuroendocrine transition. Kit pathway was directly regulated by Foxa2 and specifically activated in neuroendocrine prostate cancer (NEPC). Pharmacologic inhibition of Kit signaling significantly suppressed mouse and human NEPC tumor and organoids growth. These findings reveal that Foxa2 drives adeno-to-neuroendocrine lineage plasticity in prostate cancer, and provide a potential pharmacological strategy for castration-resistant NEPC. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sample scope | Single cell | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Release date | 2022-10-04 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Publication |
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| Grants |
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| Submitter | Fei Li (lifei6@sibcb.ac.cn) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Organization | Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Submission date | 2022-09-19 |