A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer (shRNA)
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PROVIDER: PRJNA1075691 | ENA |
REPOSITORIES: ENA
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Project description:Neuroendocrine prostate cancer (NEPC) presents a formidable clinical challenge owing to its aggressive progression and resistance to conventional therapies. A key driver of NEPC is the overexpression of MYCN, a well-established oncogene associated with neuroendocrine tumors. However, efforts to directly inhibit the N-Myc protein encoded by this gene have resulted in limited success, thereby hindering therapeutic advancements. To overcome this obstacle, we conducted unbiased genome-wide screening using isogenic prostate cancer cell lines to identify the synthetic vulnerabilities of MYCN. Among the identified candidates, NEUROG2 emerged as a significant candidate. Neurog2 is a proneural transcription factor (PTF) known for its role in developmental processes and trans-differentiation of adult cells. Our findings demonstrate that Neurog2 depletion does not affect non-malignant cells but significantly suppresses the growth of MYCN-overexpressing cells and tumors in orthotopic NEPC models. Furthermore, our observations indicate that Neurog2-driven modulation of PTFs potentially contribute to NEPC development. Thus, targeting Neurog2 holds promise as an effective therapeutic strategy for MYCN-overexpressing NEPC.
2025-04-29 | GSE255592 | GEO
Project description:Neuroendocrine prostate cancer (NEPC) presents a formidable clinical challenge owing to its aggressive progression and resistance to conventional therapies. A key driver of NEPC is the overexpression of MYCN, a well-established oncogene associated with neuroendocrine tumors. However, efforts to directly inhibit the N-Myc protein encoded by this gene have resulted in limited success, thereby hindering therapeutic advancements. To overcome this obstacle, we conducted unbiased genome-wide screening using isogenic prostate cancer cell lines to identify the synthetic vulnerabilities of MYCN. Among the identified candidates, NEUROG2 emerged as a significant candidate. Neurog2 is a proneural transcription factor (PTF) known for its role in developmental processes and trans-differentiation of adult cells. Our findings demonstrate that Neurog2 depletion does not affect non-malignant cells but significantly suppresses the growth of MYCN-overexpressing cells and tumors in orthotopic NEPC models. Furthermore, our observations indicate that Neurog2-driven modulation of PTFs potentially contribute to NEPC development. Thus, targeting Neurog2 holds promise as an effective therapeutic strategy for MYCN-overexpressing NEPC.
2025-04-29 | GSE255591 | GEO
Project description:A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer
| PRJNA1075686 | ENA
Project description:A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer (CRISPR)
| PRJNA1075693 | ENA
Project description:MYCN overexpression is a hallmark of many tumors originating from neural cell precursors. We generated a transgenic mouse with Cre-conditional induction of MYCN in glial fibre acidic protein (GFAP) expressing cells resulting in the development of neuroendocrine tumors of the pancreas and the brain. The expression profiles of nine tumors from pancreas and three brain tumors were compared to non-malignant pancreas controls (GSM771025.CEL-GSM771027.CEL) from wildtype mice Expression profiles of tumors and controls were analysed using GSEA and ANOVA.
2016-03-01 | E-GEOD-73466 | biostudies-arrayexpress
Project description:MYCN overexpression is a hallmark of many tumors originating from neural cell precursors. We generated a transgenic mouse with Cre-conditional induction of MYCN in glial fibre acidic protein (GFAP) expressing cells resulting in the development of neuroendocrine tumors of the pancreas and the brain.
2016-03-01 | GSE73466 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-04-29 | GSE255593 | GEO
Project description:Neuroendocrine and tuft cells are rare, chemosensory epithelial lineages defined by expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes. The mechanisms driving neuroendocrine–tuft tumour heterogeneity, and the origins of tuft-like cancers are unknown. Using multiple genetically-engineered animal models of SCLC, we demonstrate that a basal cell of origin (but not the accepted neuroendocrine origin) generates neuroendocrine–tuft-like tumours that highly recapitulate human SCLC. Single-cell clonal analyses of basal-derived SCLC further uncovers unexpected transcriptional states and lineage trajectories underlying neuroendocrine–tuft plasticity. Uniquely in basal cells, introduction of genetic alterations enriched in human tuft-like SCLC, including high MYC, PTEN loss, and ASCL1 suppression, cooperate to promote tuft-like tumours. Transcriptomics of 944 human SCLCs reveal a basal-like subset and a tuft-ionocyte-like state that altogether demonstrate remarkable conservation between cancer states and normal basal cell injury response mechanisms. Together, these data suggest that the basal cell is a plausible origin for SCLC and other neuroendocrine-tuft cancers that can explain neuroendocrine–tuft heterogeneity—offering new insights for targeting lineage plasticity.
2025-07-01 | GSE279200 | GEO
Project description:Neuroendocrine prostate cancer (NEPC) is a highly aggressive malignancy of increasing prevalence with an unmet need for targeted therapeutic approaches. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC; however, there is no known role for MUC1-C in driving lineage plasticity to these advanced PC phenotypes. The present studies demonstrate that upregulation of MUC1-C in androgen-independent (AI) PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor by a previously unrecognized MYC-mediated mechanism. MUC1-C activates the BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP), which are linked to NEPC progression. We also show that MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Of potential clinical relevance, targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, supporting the treatment of CRPC and NEPC with agents directed against this oncoprotein. These findings and the demonstration that MUC1-C is upregulated and associated with suppression of AR signaling, and increases in BRN2 expression and the NEPC score in PC tissues highlight the unanticipated importance of MUC1-C as a master effector of lineage plasticity in progression to advanced PC with NE features.
2019-12-02 | GSE139335 | GEO
Project description:The proneural NEUROG2 is essential for neuronal commitment, cell cycle exit and neuronal differentiation. Characterizing genes networks regulated downstream of NEUROG2 is therefore of prime importance. To identify NEUROG2 early response genes, we combined gain of function in the neural tube with a global detection of modified transcripts using microarrays. We included in our study a mutant form of NEUROG2 (NEUROG2AQ) that cannot bind DNA and cannot trigger neurogenesis. Using this approach, we identified 942 genes modified at the onset of NEUROG2 activation. The global analysis of functions regulated by NEUROG2 allowed unmasking its rapid impact on cell cycle control. We found that NEUROG2 specifically represses a subset of cyclins acting at the G1 and S phases of the cell cycle, thereby impeding S phase re-entry. This repression occurs before modification of p27kip1, indicating that the decision to leave the cell cycle precedes the activation of this Cyclin-dependant Kinase Inhibitor. Moreover, NEUROG2 down-regulates only one of the D-type cyclins, cyclinD1, and maintaining cyclinD1 blocks the ability of the proneural to trigger cell cycle exit, without altering its capacity to trigger neuronal differentiation. The fact that NEUROG2 represses a subset but not all cell cycle regulators indicates that cell cycle exit is not an indirect consequence of neuronal differentiation but is precisely controlled by NEUROG2. Altogether our findings indicate that NEUROG2, by specifically repressing G1 and S cyclins, allows committed neuronal precursors to perform their last mitosis but blocks their re-entry in the cell cycle, thus favouring cell cycle exit. Stage HH10-11 embryos (11 to 15 somites) were electroporated with a control vector (pGIG-GFP), a NEUROG2-expressing vector (pCIGNEUROG2-GFP), or a NEUROG2AQ-expressing vector (pCIGNEUROG2AQ-GFP). For each biological replicate, neural tubes from 20 embryos were pooled for GFP+ cells collection. GFP+ cells were collected 6h later using FACS sorting (Epics Altra HSS cell sorter, Toulouse Rio platform) and processed for RNA probe preparation and hybridization on Affymetrix microarrays. For each experimental condition, four biological replicates were processed.
2012-05-04 | E-GEOD-37782 | biostudies-arrayexpress