Compromised epigenetic robustness in cancer: fueling evolution, exposing weakness

Trends in cancer, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

The complex network of proteins that regulate chromatin and DNA methylation landscapes is often disrupted in cancer. Clonal subclonal mutations targeting a wide range molecular functions are frequently observed across cancer types, emerging evidence suggests loss robust epigenetic control promotes both initiation evolution, independently context-specific effects. Here, we review how diverse genetic alterations destabilize the regulatory (ERN) may converge into common phenotypes. We also discuss implications altered topology systemic disorder for vulnerability, therapeutic resistance cancers.

Language: Английский

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GRHL2-HER3 and E-cadherin mediate EGFR-bypass drug resistance in lung cancer cells

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 17, 2025

Epidermal growth factor receptor (EGFR) is a major oncogenic protein, and thus EGFR-targeting therapies are widely used in patients with various types of cancer, including lung cancer. However, resistance to EGFR inhibitors, such as erlotinib, presents significant challenge treating In this study, we established an EGFR-independent, erlotinib-resistant (ER) phenotype cancer A549 cells by exposing them erlotinib for extended period. The resulting ER exhibited dramatic increase resistance, decreased protein level, enhanced tumor growth, suggesting robust mechanism bypassing inhibition. RNA sequencing identified the transcription GRHL2 critical player resistance. was upregulated cells, its knockdown knockout significantly reduced Further analysis revealed that upregulates tyrosine kinase HER3, HER3 similarly decreases IC50 erlotinib. Additionally, showed increased cell-cell adhesion, linked E-cadherin. E-cadherin found be vital largely independent GRHL2, highlighting multiple parallel pathways sustaining These findings provide novel drug suggest combination targeting both GRHL2-HER3 E-cadherin-mediated may necessary overcome

Language: Английский

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Epigenomics‐guided precision oncology: Chromatin variants in prostate tumor evolution

International Journal of Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

Abstract Prostate cancer is a common malignancy that in 5%–30% leads to treatment‐resistant and highly aggressive disease. Metastasis‐potential treatment‐resistance thought rely on increased plasticity of the cells—a mechanism whereby cells alter their identity adapt changing environments or therapeutic pressures create cellular heterogeneity. To understand molecular basis this plasticity, genomic studies have uncovered genetic variants capture clonal heterogeneity primary tumors metastases. As largely driven by non‐genetic events, complementary epigenomics are now being conducted identify chromatin . These variants, defined as loci show changes state due loss gain epigenomic marks, inclusive histone post‐translational modifications, DNA methylation considered fundamental units In prostate hold promise guiding new era precision oncology. review, we explore role cancer, focusing how contribute tumor evolution therapy resistance. We therefore discuss impact stochastic highlighting value single‐cell sequencing liquid biopsy assays uncover targets biomarkers. Ultimately, review aims support oncology, utilizing insights from improve patient outcomes.

Language: Английский

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KLF4 promotes a KRT13+ hillock-like state in squamous lung cancer

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Lung squamous cell carcinoma (LUSC) is basal-like subtype of lung cancer with limited treatment options. While prior studies have identified tumor-propagating states in tumors, the broader landscape intra-tumoral heterogeneity within LUSC remains poorly understood. Here, we employ Sox2-driven mouse models, organoid cultures, and single-cell transcriptomic analyses to uncover previously unrecognized levels fate diversity LUSC. Specifically, identify a KRT13 + hillock-like population slower-dividing tumor cells characterized by immunomodulatory gene expression signatures. The state conserved across multiple animal models present majority human LUSCs as well head neck esophageal tumors. Our findings shed light on cellular origins states: normal club give rise tumors luminal populations, while transition into basal states, resembling homeostatic responses injury. Mechanistically, KLF4 key transcriptional regulator state, both necessary sufficient induce expression. Together, these results provide new molecular insights plasticity that underlies LUSC, offering potential avenues for therapeutic strategies.

Language: Английский

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CRISPR/Cas-mediated macromolecular DNA methylation editing: Precision targeting of DNA methyltransferases in cancer therapy

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 142401 - 142401

Published: March 1, 2025

Language: Английский

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A hitchhiker's guide to single‐cell epigenomics: Methods and applications for cancer research

International Journal of Cancer, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 22, 2024

Abstract Genetic mutations are well known to influence tumorigenesis, tumor progression, treatment response and relapse, but the role of epigenetic variation in cancer progression is still largely unexplored. The lack understanding evolution part due limited availability methods examine such a heterogeneous disease. However, last decade development several single‐cell profile diverse chromatin features (chromatin accessibility, histone modifications, DNA methylation, etc.) has propelled study epigenomics. In this review, we detail current landscape single‐omic multi‐omic with particular focus on examination modifications. Furthermore, provide recommendations both application these research how perform initial computational analyses. Together, review serves as referential framework for incorporating an important tool biology.

Language: Английский

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Population-Level Cell Trajectory Inference Based on Gaussian Distributions

Biomolecules, Journal Year: 2024, Volume and Issue: 14(11), P. 1396 - 1396

Published: Nov. 1, 2024

In the past decade, inferring developmental trajectories from single-cell data has become a significant challenge in bioinformatics. RNA velocity, with its incorporation of directional dynamics, significantly advanced study trajectories. However, as sequencing technology evolves, it generates complex, high-dimensional high noise levels. Existing trajectory inference methods, which overlook cell distribution characteristics, may perform inadequately under such conditions. To address this, we introduce CPvGTI, Gaussian distribution-based method. CPvGTI utilizes mixture model, optimized by Expectation-Maximization algorithm, to construct new populations original space. By integrating employs Process Regression analyze differentiation these populations. evaluate performance assess CPvGTI's against several state-of-the-art methods using four structurally diverse simulated datasets and real datasets. The simulation studies indicate that excels pseudo-time prediction structural reconstruction compared existing methods. Furthermore, discovery branch human forebrain mouse hematopoiesis confirms superior performance.

Language: Английский

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Cancer memory as a mechanism to establish malignancy

Biosystems, Journal Year: 2024, Volume and Issue: unknown, P. 105381 - 105381

Published: Dec. 1, 2024

Language: Английский

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