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

Park, Jung Wook; Lee, John K.; Sheu, Katherine M.; Wang, Liang; Balanis, Nikolas G.; Nguyễn, Kim; Smith, Bryan; Cheng, Chen; Tsai, Brandon L.; Cheng, Donghui; Huang, Jiaoti; Kurdistani, Siavash K.; Graeber, Thomas G.; Witte, Owen N.

doi:10.1126/science.aat5749

Cited by 252 publications

(250 citation statements)

References 50 publications

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“…The recent introduction of therapies that better target the androgen axis has led to a significant increase in frequency of castrate-resistant prostate cancer with neuroendocrine differentiation 8 . It has been shown that inactivation of the RB1 tumor suppressor gene increases cell plasticity along with the promotion of an aggressive neuroendocrine phenotype 19,27,32 . In castrated mice with combined Pten and Trp53 deficiency some prostate tumors arising from luminal cells had regions of highly proliferative cells with overt neuroendocrine differentiation.…”

Section: Discussionmentioning

confidence: 99%

Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells

Cheng

Zhou

Stone

et al. 2019

Preprint

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Aberrant neuroendocrine signaling is frequent yet poorly understood feature of prostate cancers. Membrane metalloendopeptidase (MME) is responsible for the catalytic inactivation of neuropeptide substrates, and is downregulated in nearly 50% of prostate cancers. However its role in prostate carcinogenesis, including formation of castration-resistant prostate carcinomas, remains uncertain. Here we report that MME cooperates with PTEN in suppression of carcinogenesis by controlling activities of prostate stem/progenitor cells. Lack of MME and PTEN results in development of adenocarcinomas characterized by propensity for vascular invasion and formation of proliferative neuroendocrine clusters after castration. Effects of MME on prostate stem/progenitor cells depend on its catalytic activity and can be recapitulated by addition of the MME substrate, gastrin-releasing peptide (GRP). Knockdown or inhibition of GRP receptor (GRPR) abrogate effects of MME deficiency, and delay growth of human prostate cancer xenografts by reducing the number of cancer propagating cells. In sum, our study provides a definitive proof of tumor suppressive role of MME, links GRP/GRPR signaling to the control of prostate stem/progenitor cells, and shows how dysregulation of such signaling may promote formation of castrationresistant prostate carcinomas. It also identifies GRPR as a valuable target for therapies aimed at eradication of cancer propagating cells in prostate cancers with MME downregulation.

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Section: Discussionmentioning

confidence: 99%

Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells

Cheng

Zhou

Stone

et al. 2019

Preprint

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“…For example, the combination of oncogenes required to transform cells to the most common prostate or lung cancer forms is not known. However, both primary prostate and lung epithelial cells can be transformed to small cell neuroendocrine carcinoma, suggesting that either a minority population of neuroendocrine cells are susceptible for transformation, or that both types of primary cells assume a neuroendocrine fate after transformation 43 .…”

Section: );mentioning

confidence: 99%

Cellular transformation by combined lineage conversion and oncogene expression

Sahu

Pihlajamaa

Zhang

et al. 2019

Preprint

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Cancer is the most complex genetic disease known, with mutations in more than 250 genes contributing to different forms of the disease 1,2,3 . Most human driver mutations are specific to particular types of cancer, at least in part due to differences in expression pattern between cell types, and the diversity of mutational mechanisms across different human tissues 4 . However, the fact that many apparently oncogenic mutations fail to transform differentiated cells in culture suggests that tumorigenesis is triggered by a specific combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Here we show that a combination of oncogenes that is characteristic of liver cancer cells (CTNNB1, TERT and MYC) induces cellular senescence in human fibroblasts, and in primary human hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps) makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. Temporal analysis of the tumorigenic program using single-cell RNA-seq and RNA velocity analysis revealed that the cells progress along a common path to transformation, invariably acquiring liver progenitor cell identity prior to expressing markers characteristic of liver tumor cells. These results, together with analysis of chromatin accessibility using ATAC-seq and NaNoMe-seq indicate that lineage-determining factors act by defining a cell fate and associated chromatin state that are permissive for transformation. Taken together, our results indicate that cell identity is a key determinant in transformation, and establish a paradigm for defining the molecular states of distinct types of human cancer.Cancer genetics and genomics have identified a large number of genes implicated in human cancer 1,2,3 . Although some genes such as p53 and PTEN are commonly mutated in many different types of cancer, most cancer genes are more lineage-specific. It is well

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“…Emerging evidence suggests that t‐NEPC is derived from AdPC, and this transition can occur as a result of NE differentiation. Several studies have reported that AdPC and t‐NEPC tumors have similar genotypes (ie, somatic copy number, point mutations, and polyploidy), while their transcriptome, epigenome, and cellular morphologies differ . In recent studies, we have shown that a pre‐mRNA splicing factor, SRRM4, can drive NE differentiation to transform LNCaP AdPC cells into t‐NEPC tumors by reprogramming the transcriptome through alternative RNA splicing under ARPI .…”

Section: Introductionmentioning

confidence: 97%

“…Several studies have reported that AdPC and t-NEPC tumors have similar genotypes (ie, somatic copy number, point mutations, and polyploidy), while their transcriptome, epigenome, and cellular morphologies differ. [5][6][7][8] In recent studies, we have shown that a pre-mRNA splicing factor, SRRM4, can drive NE differentiation to transform LNCaP AdPC cells into t-NEPC tumors by reprogramming the transcriptome through alternative RNA splicing under ARPI. 9 This report established a new NEPC cell model, called LnNE, which uses SRRM4-overexpressing LNCaP cells to create five generations of xenografts and cell models.…”

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confidence: 99%

Alternative RNA splicing of the GIT1 gene is associated with neuroendocrine prostate cancer

et al. 2018

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Potent androgen receptor pathway inhibition (ARPI) therapies have given rise to a lethal, aggressive subtype of castration‐resistant prostate cancer (CRPC) called treatment‐induced neuroendocrine prostate cancer (t‐NEPC). Now, t‐NEPC poses a major clinical problem as approximately 20% of CRPC cases bear this subtype—a rate of occurrence that is predicted to rise with the widespread use of ARPI therapies. Unfortunately, there are no targeted therapies currently available to treat t‐NEPC as the origin and molecular underpinnings of t‐NEPC development remain unclear. In the present study, we identify that RNA splicing of the G protein‐coupled receptor kinase‐interacting protein 1 (GIT1) gene is a unique event in t‐NEPC patients. Specifically, upregulation of the GIT1‐A splice variant and downregulation of the GIT1‐C variant expressions are associated with t‐NEPC patient tumors, patient‐derived xenografts, and cell models. RNA‐binding assays show that RNA splicing of GIT1 is directly driven by SRRM4 and is associated with the neuroendocrine phenotype in CRPC cohorts. We show that GIT1‐A and GIT1‐C regulate differential transcriptomes in prostate cancer cells, where GIT1‐A regulates genes associated with morphogenesis, neural function, environmental sensing via cell‐adhesion processes, and epigenetic regulation. Consistent with our transcriptomic analyses, we report opposing functions of GIT1‐A and GIT1‐C in the stability of focal adhesions, whereby GIT1‐A promotes focal adhesion stability. In summary, our study is the first to report that alternative RNA splicing of the GIT1 gene is associated with t‐NEPC and reprograms its function involving FA‐mediated signaling and cell processes, which may contribute to t‐NEPC development.

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

Cited by 252 publications

References 50 publications

Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells

Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells

Cellular transformation by combined lineage conversion and oncogene expression

Alternative RNA splicing of the GIT1 gene is associated with neuroendocrine prostate cancer

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