ERG-driven prostate cancer initiation is cell-context dependent and requires KMT2A and DOT1L Journal Article
| Authors: | Feng, W. R.; Ladewig, E.; Lange, M.; Salsabeel, N.; Zhao, H. Y.; Lee, Y. S.; Gopalan, A.; Luo, H. Z.; Kang, W. F.; Fan, N.; Rosiek, E.; de Stanchina, E.; Chen, Y.; Carver, B. S.; Leslie, C. S.; Sawyers, C. L. |
| Article Title: | ERG-driven prostate cancer initiation is cell-context dependent and requires KMT2A and DOT1L |
| Abstract: | Despite the high prevalence of ERG transcription factor translocations in prostate cancer, the mechanism of tumorigenicity remains poorly understood. Using lineage tracing, we find the tumor-initiating activity of ERG resides in a subpopulation of murine basal cells that coexpress luminal genes (BasalLum) and not in the larger population of ERG+ luminal cells. Upon ERG activation, BasalLum cells give rise to highly proliferative intermediate (IM) cells with stem-like features that coexpress basal, luminal, hillock and club marker genes, before transitioning to Krt8+ luminal cells. Transcriptomic analysis of ERG+ human prostate cancers confirms the presence of rare ERG+ BasalLum cells, as well as IM cells whose presence is associated with a worse prognosis. Single-cell analysis revealed a chromatin state in ERG+ IM cells enriched for STAT3 transcription factor binding sites and elevated expression of the KMT2A/MLL1 and DOT1L, all three of which are essential for ERG-driven tumorigenicity in vivo. In addition to providing translational opportunities, this work illustrates how single-cell approaches combined with lineage tracing can identify cancer vulnerabilities not evident from bulk analysis. |
| Keywords: | transcription factors; differentiation; stem-cells; mouse model; epithelial-cells; basal-cells; tmprss2-erg gene fusion; luminal cells; androgen receptor cistrome; adult human prostate |
| Journal Title: | Nature Genetics |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Publication status: | Online ahead of print |
| Date Published: | 2025-01-01 |
| Online Publication Date: | 2025-01-01 |
| Language: | English |
| ACCESSION: | WOS:001556823700001 |
| DOI: | 10.1038/s41588-025-02289-w |
| PROVIDER: | wos |
| Notes: | Article; Early Access -- Source: Wos |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work