Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(7)

Опубликована: Фев. 6, 2024

Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular rhythms noncancerous cancerous human tissues their clinical relevance are largely unknown. We reconstructed informatically, integrating locally collected, time-stamped biopsies with public datasets. For tissue, inflammatory, epithelial–mesenchymal transition (EMT), estrogen responsiveness pathways show modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes organization. Luminal A organoids informatic ordering of luminal samples exhibit continued, albeit dampened reprogrammed rhythms. CYCLOPS magnitude, a measure global rhythm strength, varied widely among samples. Cycling EMT pathway genes was markedly increased high-magnitude tumors. Surprisingly, patients tumors had reduced 5-y survival. Correspondingly, 3D cultures invasion following disruption. This study links cancer EMT, metastatic potential, prognosis.

Язык: Английский

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Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer

Cell Reports, Год журнала: 2025, Номер 44(2), С. 115267 - 115267

Опубликована: Фев. 1, 2025

Hypoxia influences the epithelial-mesenchymal transition (EMT) through remodeling of chromatin structure, epigenetics, and alternative splicing. drives CCCTC-binding factor (CTCF) induction hypoxia-inducible 1-alpha (HIF1α), which promotes EMT, although underlying mechanisms remain unclear. We find that hypoxia significantly increases CTCF occupancy at various EMT-related genes. present a CTCF-mediated intricate mechanism promoting EMT wherein binding collagen type V alpha 1 chain (COL5A1) promoter is crucial for COL5A1 upregulation under hypoxia. Additionally, exon64A inclusion in mutually exclusive splicing event COL5A1exon64 (exon64A/64B). Notably, mediates promoter-alternatively spliced exon upstream looping regulates DNA demethylation distal exon64A. This further RNA polymerase II pause COL5A1exon64A, leading to its Genome-wide study indicates association gained with many cancer-related genes, similar proposed model. Specifically, disrupting HIF1α-CTCF-COL5A1exon64A axis dCas9-DNMT3A system alleviates hypoxic cancer cells may represent novel therapeutic target breast cancer.

Язык: Английский

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Time series-free rhythm profiling using COFE reveals multi-omic circadian rhythms in in-vivo human cancers

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 15, 2024

The study of the ubiquitous circadian rhythms in human physiology typically requires regular measurements across time. Repeated sampling different internal tissues that house clocks is both practically and ethically infeasible. Here, we present a novel unsupervised machine learning approach (COFE) can use single high-throughput (omics) samples from individuals to reconstruct cohorts. COFE assign time-labels samples, identify rhythmic data features used for temporal reconstruction. With COFE, discovered widespread de novo gene expression eleven adenocarcinomas using TCGA database. arrangement peak times core clock was conserved cancers resembled healthy functional except mistiming few key genes. commonly genes were involved metabolism cell cycle. Although these synchronized with cycle many cancers, they uncoupled matched tissue. Moreover, transcriptome strongly associated cancer-relevant proteome. targets most FDA-approved potential anti-cancer drugs tumor tissue amplitudes times, emphasizing utility considering "time" cancer therapy. Our thus creates new opportunities repurpose without rhythms.

Язык: Английский

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Quantification of circadian rhythms in mammalian lung tissue snapshot data

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Июль 14, 2024

Abstract Healthy mammalian cells have a circadian clock, gene regulatory network that allows them to schedule their physiological processes optimal times of the day. When healthy turn into cancer cells, clock often becomes specifically disturbed, so there is an interest in extraction features from expression data cancer. This challenging, as clinical samples are snapshot-like and best examined using time series. In this study, we obtained lists intersecting genes public series lung tissue mouse baboon. We base our on correlations levels genes, which closely associated phase differences between them. Combining patterns diurnal nocturnal species different ages provides also important cancerous human tissue. tested quality representation by PCA-based reconstructions baboon samples. Then assigned potential find intact tissue, but altered, weak adjacent

Язык: Английский

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Circadian clock features define novel subtypes among breast cancer cells and shape drug sensitivity

Molecular Systems Biology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Abstract The circadian clock regulates key physiological processes, including cellular responses to DNA damage. Circadian-based therapeutic strategies optimize treatment timing enhance drug efficacy and minimize side effects, offering potential for precision cancer treatment. However, applying these in remains limited due a lack of understanding the clock’s function across types incomplete insights into how affects responses. To address this, we conducted deep phenotyping panel breast cell lines. Observing diverse dynamics, characterized metrics assess rhythm strength stability vitro. This led identification four distinct circadian-based phenotypes among 14 models: functional, weak, unstable, dysfunctional clocks. Furthermore, demonstrate that plays critical role shaping pharmacological various anti-cancer drugs identify features descriptive sensitivity. Collectively, our findings establish foundation implementing cancer, leveraging sensitivity patterns outcomes.

Язык: Английский

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Reconstructed Cell-Type Specific Rhythms in Human Brain link Alzheimer's Pathology, Circadian Stress, and Ribosomal Disruption

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 26, 2025

Alzheimer's disease (AD) disrupts behavioral circadian rhythms, but its effects on molecular rhythms in the human brain are poorly understood. Using single-nucleus RNA sequencing from post-mortem cortical samples, we informatically estimated relative phases of 409 persons with and without AD dementia. We then reconstructed expression profiles across cell types. While core clock were preserved AD, many cell-type specific outputs disrupted. Rhythms ribosomal biogenesis oxidative phosphorylation dampened Similar losses gene observed APP/PS1 mice, which showed further reductions protein polysome-mediated translation after desynchrony. Exploratory computational modeling reveals that altered may contribute to increased variability seen patients. These findings reveal output brains affected patients, highlight disrupted as a feature AD.

Язык: Английский

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Chronobiology: Circadian Rhythm and Cancer

Опубликована: Янв. 1, 2025

Язык: Английский

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Circadian Rhythm Disruption in Triple‐Negative Breast Cancer: Molecular Insights and Treatment Strategies

Journal of Pineal Research, Год журнала: 2025, Номер 77(3)

Опубликована: Апрель 1, 2025

ABSTRACT Disruption of the circadian clock has been closely linked to initiation, development, and progression cancer. This study aims explore impact rhythm disruption (CRD) on triple‐negative breast cancer (TNBC). We analyzed bulk single‐cell RNA sequencing data assess status in TNBC using multiple bioinformatic tools, alongside metabolomic profiles tumor microenvironment evaluations understand influence CRD metabolic reprogramming immune evasion. The results indicate that experiences profound CRD. Patients with a higher CRDscore exhibit significantly poorer relapse‐free survival compared those lower CRDscore. Cyclic ordering by periodic structure (CYCLOPS) identified significant changes rhythmic gene expression patterns between normal tissues, showing “rush hour” effect, where peak times are concentrated within specific time windows. Transcripts disrupted rhythms were found be involved key pathways related cell cycle regulation, metabolism, response. Metabolomic analysis further revealed TNBCs high enriched carbohydrate amino acid metabolism pathways, notably upregulation tryptophan metabolism. High was also an immunosuppressive microenvironment, characterized reduced infiltration, exhausted CD8 + T cells, diminished response checkpoint blockade therapy. These findings suggest molecular may activate thereby promoting evasion potentially reducing effectiveness immunotherapy.

Язык: Английский

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Rhythm profiling using COFE reveals multi-omic circadian rhythms in human cancers in vivo

PLoS Biology, Год журнала: 2025, Номер 23(5), С. e3003196 - e3003196

Опубликована: Май 27, 2025

The study of ubiquitous circadian rhythms in human physiology requires regular measurements across time. Repeated sampling the different internal tissues that house clocks is both practically and ethically infeasible. Here, we present a novel unsupervised machine learning approach (COFE) can use single high-throughput omics samples (without time labels) from individuals to reconstruct cohorts. COFE simultaneously assign labels identify rhythmic data features used for temporal reconstruction, while also detecting invalid orderings. With COFE, discovered widespread de novo gene expression 11 adenocarcinomas using Cancer Genome Atlas (TCGA) database. arrangement peak times core clock was conserved cancers resembled healthy functional except mistiming few key genes. Moreover, transcriptome were strongly associated with cancer-relevant proteome. genes proteins common all involved metabolism cell cycle. Although these synchronized cycle many cancers, they uncoupled matched tissue. targets most FDA-approved potential anti-cancer drugs tumor tissue amplitudes times. These findings emphasize utility considering “time" cancer therapy, suggest focus on rather than free-running Our thus creates new opportunities repurpose without rhythms.

Язык: Английский

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Can we utilise the circadian clock to target cancer stem cells?

Cancer Letters, Год журнала: 2024, Номер unknown, С. 217360 - 217360

Опубликована: Ноя. 1, 2024

Язык: Английский

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