Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage.
Jung Wook ParkJohn K LeeKatherine M SheuLiang WangNikolas G BalanisKim NguyenBryan A SmithChen ChengBrandon L TsaiDonghui ChengJiaoti HuangSiavash K KurdistaniThomas Glen GraeberOwen N WittePublished in: Science (New York, N.Y.) (2019)
The use of potent therapies inhibiting critical oncogenic pathways active in epithelial cancers has led to multiple resistance mechanisms, including the development of highly aggressive, small cell neuroendocrine carcinoma (SCNC). SCNC patients have a dismal prognosis due in part to a limited understanding of the molecular mechanisms driving this malignancy and the lack of effective treatments. Here, we demonstrate that a common set of defined oncogenic drivers reproducibly reprograms normal human prostate and lung epithelial cells to small cell prostate cancer (SCPC) and small cell lung cancer (SCLC), respectively. We identify shared active transcription factor binding regions in the reprogrammed prostate and lung SCNCs by integrative analyses of epigenetic and transcriptional landscapes. These results suggest that neuroendocrine cancers arising from distinct epithelial tissues may share common vulnerabilities that could be exploited for the development of drugs targeting SCNCs.
Keyphrases
- prostate cancer
- transcription factor
- gene expression
- small cell lung cancer
- single cell
- endothelial cells
- radical prostatectomy
- end stage renal disease
- cell therapy
- ejection fraction
- dna binding
- induced pluripotent stem cells
- newly diagnosed
- chronic kidney disease
- benign prostatic hyperplasia
- dna methylation
- signaling pathway
- papillary thyroid
- prognostic factors
- squamous cell carcinoma
- drug delivery
- young adults
- network analysis