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Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage

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Science  05 Oct 2018:
Vol. 362, Issue 6410, pp. 91-95
DOI: 10.1126/science.aat5749

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Some (re)programming notes on cancer

Epithelial cancers develop resistance to targeted therapies in a number of different ways. Several cancer types do so by undergoing phenotypic conversion to a highly aggressive cancer called small cell neuroendocrine carcinoma (SCNC). Whether distinct cancer types accomplish this “reprogramming” through the same mechanism has been unclear. Park et al. show that the same set of oncogenic factors transforms both normal lung and normal prostate epithelial cells into SCNCs that resemble clinical samples (see the Perspective by Kareta and Sage). This convergence of molecular pathways could potentially simplify the development of new therapies for SCNC, which is currently untreatable.

Science, this issue p. 91; see also p. 30

Abstract

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.

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