A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 19, 2024

Summary Neuroendocrine prostate cancer (NEPC) presents a formidable clinical challenge owing to its aggressive progression and resistance conventional therapies. A key driver of NEPC is the overexpression MYCN , well-established oncogene associated with neuroendocrine tumors. However, efforts directly inhibit N-Myc protein encoded by this gene have resulted in limited success, thereby hindering therapeutic advancements. To overcome obstacle, we conducted unbiased genome-wide screening using isogenic cell lines identify synthetic vulnerabilities . Among identified candidates, NEUROG2 emerged as significant candidate. Neurog2 proneural transcription factor (PTF) known for role developmental processes trans-differentiation adult cells. Our findings demonstrate that depletion does not affect non-malignant cells, but significantly suppresses growth -overexpressing cells tumors orthotopic models. Furthermore, our observations indicate Neurog2-mediated regulation PTFs can facilitate development. Thus, targeting holds promise an effective strategy NEPC.

Language: Английский

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Understanding the function of Pax5 in development of docetaxel-resistant neuroendocrine-like prostate cancers

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(8)

Published: Aug. 25, 2024

Abstract Resistance to the current Androgen Receptor Signaling Inhibitor (ARSI) therapies has led higher incidences of therapy-induced neuroendocrine-like prostate cancer (t-NEPC). This highly aggressive subtype with predominant small-cell-like characteristics is resistant taxane chemotherapies and a dismal overall survival. t-NEPCs are mostly treated platinum-based drugs combination etoposide or have less selectivity high systemic toxicity, which often limit their clinical potential. During t-NEPC transformation, adenocarcinomas lose luminal features adopt neuro-basal characteristics. Whether adaptive neuronal responsible for such resistance remains unknown. Pathway analysis from patient gene-expression databases indicates that upregulates various pathways associated enhanced cellular networks. To identify transcription factor(s) (TF) could be important promoting gene expression characters in t-NEPC, we performed ATAC-Seq, acetylated-histone ChIP-seq, RNA-seq our NE-like cell line models analyzed promoters transcriptionally active significantly enriched (NE-like) cancer-specific genes. Our results indicate Pax5 an factor specific t-NEPC. revealed involved axonal guidance, neurotransmitter regulation, adhesion, critical strong communications. Further suggest depletion disrupts neurite-mediated communication cells reduces surface growth receptor activation, thereby, sensitizing them docetaxel therapies. Moreover, t-NEPC-specific hydroxymethylation promoter CpG islands favors Pbx1 binding induce expression. Based on study, concluded continuous exposure ARSI leads epigenetic modifications activation promotes genes necessary taxane-resistant cancer. Thus, targeting axis can beneficial reverting sensitivity.

Language: Английский

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A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 8, 2024

Neuroendocrine prostate cancer (NEPC) presents a formidable clinical challenge owing to its aggressive progression and resistance conventional therapies. A key driver of NEPC is the overexpression MYCN, well-established oncogene associated with neuroendocrine tumors. However, efforts directly inhibit N-Myc protein encoded by this gene have resulted in limited success, thereby hindering therapeutic advancements. To overcome obstacle, we conducted unbiased genome-wide screening using isogenic cell lines identify synthetic vulnerabilities MYCN. Among identified candidates, NEUROG2 emerged as significant candidate. Neurog2 proneural transcription factor (PTF) known for role developmental processes trans-differentiation adult cells. Our findings demonstrate that depletion does not affect non-malignant cells, but significantly suppresses growth MYCN-overexpressing cells tumors orthotopic models. Furthermore, our observations indicate Neurog2-mediated regulation PTFs can facilitate development. Thus, targeting holds promise an effective strategy NEPC.

Language: Английский

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Video tracking of single cells to identify clustering behaviour

Published: Nov. 11, 2024

Abstract Cancer cell clustering is a critical factor in metastasis, with cells often believed to migrate groups as they establish themselves new environments. This study presents preliminary findings from an vitro experiment, suggesting that co-culturing provides effective method for observing this phenomenon, even though the are grown monolayers. We introduce novel single-cell tracking approach based on graph theory identify clusters PC3 cultivated both monoculture and co-culture PC12 cells, using 66-hour time-lapse recordings. The initial step consists of defining ‘linked’ pairs laying foundation application theory. propose two alternative definitions pairings. first method, Method 1 , defines at given time t if close together within defined period before after . A second potential 2 there overlap between convex hulls their respective tracks during period. Pairing enables subsequent analysis. framework represents vertex (node) relation edge. An interconnected set high-degree nodes (nodes many connections or edges) forms subgraph, backbone, patch (cluster) cells. All connected backbone part subgraph. functions partition (or cut) graph. Two consecutive video considered share same identity following cluster contains least p = 75 % preceding cluster, mean positions △ r µm. appear form persistent exceeding 10 40 50 h incubation seeding. In contrast, cultured alone (mono-culture) did not exhibit behaviour. experimental requires further validation broader dataset.

Language: Английский

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Video tracking of single cells to identify clustering behavior

Frontiers in Imaging, Journal Year: 2024, Volume and Issue: 3

Published: Dec. 2, 2024

Cancer cell clustering is a critical factor in metastasis, with cells often believed to migrate groups as they establish themselves new environments. This study presents preliminary findings from an vitro experiment, suggesting that co-culturing provides effective method for observing this phenomenon, even though the are grown monolayers. We introduce novel single-cell tracking approach based on graph theory identify clusters PC3 cultivated both monoculture and co-culture PC12 cells, using 66-h time-lapse recordings. The initial step consists of defining “linked” pairs laying foundation application theory. propose two alternative definitions pairings. first method, Method 1 , defines at given time t if close together within defined period before after . A second potential 2 there overlap between convex hulls their respective tracks during period. Pairing enables subsequent analysis. framework represents vertex (node) relation edge. An interconnected set high-degree nodes (nodes many connections or edges) forms subgraph, backbone, patch (cluster) cells. All connected backbone part subgraph. functions partition (or cut) graph. Two consecutive video considered share same identity following cluster contains least p = 75 % preceding cluster, mean positions △ r 75μm. appear form persistent exceeding 10 40–50 h incubation seeding. In contrast, cultured alone (mono-culture) did not exhibit behavior. experimental requires further validation broader dataset.

Language: Английский

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