Reprogramming Landscape Highlighted by Dynamic Transcriptomes in Therapy-induced Neuroendocrine Differentiation
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PROVIDER: PRJNA891317 | ENA |
REPOSITORIES: ENA
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Project description:Reprogramming Landscape Highlighted by Dynamic Transcriptomes in Therapy-induced Neuroendocrine Differentiation [mRNA-seq]
| PRJNA890319 | ENA
Project description:Reprogramming Landscape Highlighted by Dynamic Transcriptomes in Therapy-induced Neuroendocrine Differentiation [scRNA-seq]
| PRJNA891333 | ENA
Project description:Reprogramming Landscape Highlighted by Dynamic Transcriptomes in Therapy-induced Neuroendocrine Differentiation [CUT&RUN]
| PRJNA892111 | ENA
Project description:Metastatic and locally advanced prostate cancer is treated by pharmacological targeting of androgen synthesis and androgen response via androgen signaling inhibitors (ASI), most of which target the androgen receptor (AR). However, ASI therapy invariably fails after 1-2 years. Emerging clinical evidence indicates that in response to ASI therapy, the AR-positive prostatic adenocarcinoma can transdifferentiate into AR-negative neuroendocrine prostate cancer (NEPC) in 17-25% treated patients, likely through a process called neuroendocrine differentiation (NED). Despite high clinical incidence, the epigenetic pathways underlying NED and ASI therapy-induced NED remain unclear. By utilizing a combinatorial single cell and bulk mRNA sequencing workflow, we demonstrate in a time-resolved manner that following AR inhibition with enzalutamide, prostate cancer cells exhibit immediate loss of canonical AR signaling activity and simultaneous morphological change from epithelial to NE-like (NEL) morphology, followed by activation of specific neuroendocrine (NE)-associated transcriptional programs. Additionally, we observed that activation of NE-associated pathways occurs prior to complete repression of epithelial or canonical AR pathways, a phenomenon also observed clinically via heterogenous AR status in clinical samples. Our model indicates that, mechanistically, ASI therapy induces NED with initial morphological change followed by deactivation of canonical AR target genes and subsequent de-repression of NE-associated target genes, while retaining AR expression and transcriptional shift towards non-canonical AR activity. Coupled with scRNA-seq and CUT&RUN analysis, our model system can provide a platform for screening of potential therapeutic agents that may prevent ASI-induced NED or reverse the NED process.
2022-10-28 | GSE216118 | GEO
Project description:Metastatic and locally advanced prostate cancer is treated by pharmacological targeting of androgen synthesis and androgen response via androgen signaling inhibitors (ASI), most of which target the androgen receptor (AR). However, ASI therapy invariably fails after 1-2 years. Emerging clinical evidence indicates that in response to ASI therapy, the AR-positive prostatic adenocarcinoma can transdifferentiate into AR-negative neuroendocrine prostate cancer (NEPC) in 17-25% treated patients, likely through a process called neuroendocrine differentiation (NED). Despite high clinical incidence, the epigenetic pathways underlying NED and ASI therapy-induced NED remain unclear. By utilizing a combinatorial single cell and bulk mRNA sequencing workflow, we demonstrate in a time-resolved manner that following AR inhibition with enzalutamide, prostate cancer cells exhibit immediate loss of canonical AR signaling activity and simultaneous morphological change from epithelial to NE-like (NEL) morphology, followed by activation of specific neuroendocrine (NE)-associated transcriptional programs. Additionally, we observed that activation of NE-associated pathways occurs prior to complete repression of epithelial or canonical AR pathways, a phenomenon also observed clinically via heterogenous AR status in clinical samples. Our model indicates that, mechanistically, ASI therapy induces NED with initial morphological change followed by deactivation of canonical AR target genes and subsequent de-repression of NE-associated target genes, while retaining AR expression and transcriptional shift towards non-canonical AR activity. Coupled with scRNA-seq and CUT&RUN analysis, our model system can provide a platform for screening of potential therapeutic agents that may prevent ASI-induced NED or reverse the NED process.
2022-10-28 | GSE215943 | GEO
Project description:Metastatic and locally advanced prostate cancer is treated by pharmacological targeting of androgen synthesis and androgen response via androgen signaling inhibitors (ASI), most of which target the androgen receptor (AR). However, ASI therapy invariably fails after 1-2 years. Emerging clinical evidence indicates that in response to ASI therapy, the AR-positive prostatic adenocarcinoma can transdifferentiate into AR-negative neuroendocrine prostate cancer (NEPC) in 17-25% treated patients, likely through a process called neuroendocrine differentiation (NED). Despite high clinical incidence, the epigenetic pathways underlying NED and ASI therapy-induced NED remain unclear. By utilizing a combinatorial single cell and bulk mRNA sequencing workflow, we demonstrate in a time-resolved manner that following AR inhibition with enzalutamide, prostate cancer cells exhibit immediate loss of canonical AR signaling activity and simultaneous morphological change from epithelial to NE-like (NEL) morphology, followed by activation of specific neuroendocrine (NE)-associated transcriptional programs. Additionally, we observed that activation of NE-associated pathways occurs prior to complete repression of epithelial or canonical AR pathways, a phenomenon also observed clinically via heterogenous AR status in clinical samples. Our model indicates that, mechanistically, ASI therapy induces NED with initial morphological change followed by deactivation of canonical AR target genes and subsequent de-repression of NE-associated target genes, while retaining AR expression and transcriptional shift towards non-canonical AR activity. Coupled with scRNA-seq and CUT&RUN analysis, our model system can provide a platform for screening of potential therapeutic agents that may prevent ASI-induced NED or reverse the NED process.
2022-10-28 | GSE215653 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-10-28 | GSE215945 | GEO
Project description:<p>NAMPT plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells was associated with down-regulation of genes relevant to QPRT-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also found that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but NMRK1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations was synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.</p><p><br></p><p><strong>Mouse NAMPT targeted therapy</strong> is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS7252' rel='noopener noreferrer' target='_blank'><strong>MTBLS7252</strong></a>.</p><p><strong>Cell NAMPTi treatment </strong>is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7251' rel='noopener noreferrer' target='_blank'><strong>MTBLS7251</strong></a>.</p><p><strong>Mouse NAD targeted time-course</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7253' rel='noopener noreferrer' target='_blank'><strong>MTBLS7253</strong></a>.</p>
2023-10-10 | MTBLS7252 | MetaboLights
Project description:Small cell lung cancer (SCLC) is a neuroendocrine tumor treated clinically as a single disease with poor outcomes. Distinct SCLC molecular subtypes have been defined based on expression of lineage-related transcription factors: ASCL1, NEUROD1, POU2F3 or YAP1, but their origins remain unknown. We developed an in vitro model of MYC-driven SCLC tumor cell progression, and performed a time-series analysis of single-cell transcriptome profiling to reveal that MYC drives the dynamic evolution of SCLC subtypes. Analyses of these single-cell RNA seq data reveal that MYC promotes a temporal shift from an ASCL1-to-NEUROD1-to-YAP1+ state from a neuroendocrine cell of origin. MYC activates Notch signaling to dedifferentiate tumor cells to non-neuroendocrine fates. Additional single-cell RNA sequencing of 4RPM tumors reveal individual tumors to consist of cells at nearly every stage of RPM tumor evolution modeled in vitro. With the single-cell RNA sequencing of this human SCLC liver biopsy, along with IHC on a panel of 21 human biopsies, we show that human SCLC exhibits intratumoral SCLC subtype heterogeneity, suggesting this dynamic evolution occurs in patient tumors. Together, these single-cell RNA sequencing data support our conclusions that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.
2020-05-28 | GSE150766 | GEO
Project description:Small cell lung cancers (SCLC) rapidly resist cytotoxic chemotherapy and immune-checkpoint inhibitor (ICI) treatments. New, non-cross-resistant therapies are thus needed. SCLC cells are committed into neuroendocrine-lineage then maturation-arrested. The corepressor DNA methyltransferase 1 (DNMT1) mediates the maturation-arrests: (i) the repression mark methylated-CpG, written by DNMT1, is retained at suppressed neuroendocrine-lineage genes, even as other repression marks are erased; (ii) DNMT1 is recurrently amplified, while Ten-Eleven-Translocation 2 (TET2) that functionally opposes DNMT1 is deleted; (iii) DNMT1 is recruited into neuroendocrine-lineage master transcription factor (ASCL1, NEUROD1) hubs in SCLC cells; and (iv) DNMT1 knock-down activated ASCL1-target genes and released SCLC cell cycling exits by terminal lineage-maturation, cycling exits that do not require the p53/apoptosis-pathway used by cytotoxic chemotherapy. Inhibiting DNMT1/corepressors with clinical compounds accordingly extended survival of mice with chemo- and ICI-refractory disseminated SCLC. Neuroendocrine-lineage commitment of SCLC cells can thus be leveraged into p53/apoptosis-independent therapy, active against chemo- and ICI-refractory SCLC.
2023-07-25 | GSE238006 | GEO