The epithelial–mesenchymal plasticity landscape: principles of design and mechanisms of regulation

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(9), P. 590 - 609

Published: May 11, 2023

Language: Английский

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Aberrant protein glycosylation: Implications on diagnosis and Immunotherapy

Biotechnology Advances, Journal Year: 2023, Volume and Issue: 66, P. 108149 - 108149

Published: April 6, 2023

Glycosylation-mediated post-translational modification is critical for regulating many fundamental processes like cell division, differentiation, immune response, and cell-to-cell interaction. Alterations in the N-linked or O-linked glycosylation pattern of regulatory proteins transcription factors cellular receptors lead to diseases, including cancer. These alterations give rise micro- macro-heterogeneity tumor cells. Here, we review role O- its function autoimmunity aberrant The change glycome could result from a expression glycosidases glycosyltransferases N-acetyl-glucosaminyl transferase V, FUT8, ST6Gal-I, DPAGT1, etc., impact target leading transformation. Moreover, mutations glycogenes affect patterns on cells other related manifestations pro- anti-inflammatory effects. In recent years, understanding cancer indicates that it can be utilized both diagnosis/prognosis as well immunotherapy. Studies involving mass spectrometry proteome, site- structure-specific glycoproteomics, transcriptomics/genomics patient samples models revealed importance homeostasis biology. development emerging technologies, such lectin microarray, has facilitated research structure glycans glycosylation. Newly developed devices allow high-throughput, high-speed, precise This paper also discusses technologies clinical applications

Language: Английский

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Cancer drug-tolerant persister cells: from biological questions to clinical opportunities

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(10), P. 694 - 717

Published: Sept. 2, 2024

Language: Английский

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A partial epithelial‐mesenchymal transition signature for highly aggressive colorectal cancer cells that survive under nutrient restriction

The Journal of Pathology, Journal Year: 2024, Volume and Issue: 262(3), P. 347 - 361

Published: Jan. 18, 2024

Abstract Partial epithelial‐mesenchymal transition (p‐EMT) has recently been identified as a hybrid state consisting of cells with both epithelial and mesenchymal characteristics is associated the migration, metastasis, chemoresistance cancer cells. Here, we describe induction p‐EMT in starved colorectal (CRC) identify gene signature that can predict prognosis. Functional characterisation starvation‐induced HCT116, DLD1, HT29 showed changes proliferation, morphology, drug sensitivity, supported by vivo studies using chorioallantoic membrane model. An EMT‐specific quantitative polymerase chain reaction (qPCR) array was used to screen for deregulated genes, leading establishment an silico correlated poor disease‐free survival CRC patients along consensus molecular subtype CMS4. Among significantly triple‐gene SERPINE1 , SOX10 epidermal growth factor receptor ( EGFR ) identified. Starvation‐induced characterised increased migratory potential chemoresistance, well E‐cadherin processing internalisation. Both alterations could be reversed proteasomal inhibitor MG132. Spatially resolving expression high‐resolution immunofluorescence imaging proliferation stop caused In conclusion, have gained insight into previously undiscovered EMT mechanism may become relevant when tumour are under nutrient stress, seen early stages metastasis. Targeting this process cell dissemination might help prevent overcome resistance. © 2024 The Authors. Journal Pathology published John Wiley & Sons Ltd on behalf Pathological Society Great Britain Ireland.

Language: Английский

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Epigenetic memory acquired during long-term EMT induction governs the recovery to the epithelial state

Journal of The Royal Society Interface, Journal Year: 2023, Volume and Issue: 20(198)

Published: Jan. 1, 2023

Epithelial–mesenchymal transition (EMT) and its reverse mesenchymal–epithelial (MET) are critical during embryonic development, wound healing cancer metastasis. While phenotypic changes short-term EMT induction reversible, long-term has been often associated with irreversibility. Here, we show that seen in MCF10A cells upon by TGF β need not be irreversible, but have relatively longer time scales of reversibility than those induction. Next, using a phenomenological mathematical model to account for the chromatin-mediated epigenetic silencing miR-200 family ZEB family, highlight how memory gained can slow recovery epithelial state post-TGF withdrawal. Our results suggest modifiers govern extent scale advise caution against labelling as ‘irreversible’.

Language: Английский

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Synthetic Epigenetic Reprogramming of Mesenchymal to Epithelial States Using the CRISPR/dCas9 Platform in Triple Negative Breast Cancer

Advanced Science, Journal Year: 2023, Volume and Issue: 10(22)

Published: May 22, 2023

Epithelial-mesenchymal transition (EMT) is a reversible transcriptional program invoked by cancer cells to drive progression. Transcription factor ZEB1 master regulator of EMT, driving disease recurrence in poor-outcome triple negative breast cancers (TNBCs). Here, this work silences TNBC models CRISPR/dCas9-mediated epigenetic editing, resulting highly-specific and nearly complete suppression vivo, accompanied long-lasting tumor inhibition. Integrated "omic" changes promoted dCas9 linked the KRAB domain (dCas9-KRAB) enabled discovery ZEB1-dependent-signature 26 genes differentially-expressed -methylated, including reactivation enhanced chromatin accessibility cell adhesion loci, outlining reprogramming toward more epithelial state. In locus silencing associated with induction locally-spread heterochromatin, significant DNA methylation at specific CpGs, gain H3K9me3, near erasure H3K4me3 promoter. Epigenetic shifts induced ZEB1-silencing are enriched subset human tumors, illuminating clinically-relevant hybrid-like Thus, synthetic epi-silencing induces stable "lock-in" mesenchymal tumors distinct landscape. This outlines epigenome-engineering approaches for reversing EMT customizable precision molecular oncology targeting poor outcome cancers.

Language: Английский

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Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma

Nature Biomedical Engineering, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 10, 2024

In patients with pancreatic ductal adenocarcinoma (PDAC), intratumoural and intertumoural heterogeneity increases chemoresistance mortality rates. However, such morphological phenotypic diversities are not typically captured by organoid models of PDAC. Here we show that branched organoids embedded in collagen gels can recapitulate the landscape seen murine human PDAC, pronounced molecular is governed defined transcriptional programmes (notably, epithelial-to-mesenchymal plasticity), different phenotypes represent distinct tumour-cell states unique biological features vivo. We also phenotype-specific therapeutic vulnerabilities modes treatment-induced phenotype reprogramming be maps. Our methodology analyses PDAC may guide development phenotype-targeted treatment strategies.

Language: Английский

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An integrative phenotype-structured partial differential equation model for the population dynamics of epithelial-mesenchymal transition

npj Systems Biology and Applications, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 6, 2025

Phenotypic heterogeneity along the epithelial-mesenchymal (E-M) axis contributes to cancer metastasis and drug resistance. Recent experimental efforts have collated detailed time-course data on emergence dynamics of E-M in a cell population. However, it remains unclear how different intra- inter-cellular processes shape heterogeneity. Here, using Cell Population Balance model, we capture density phenotypic resulting from interplay between-(a) intracellular regulatory interaction among biomolecules, (b) division death (c) stochastic cell-state transition. We find that while existence depends regulation, gets enhanced with transitions diminished by growth rate differences. Further, resource competition cells can lead both bi-phasic total population and/or bi-stability composition. Overall, our model highlights complex between cellular shaping dynamic patterns

Language: Английский

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A Model of Epigenetic Inheritance Accounts for Unexpected Adaptation to Unforeseen Challenges

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Abstract Accumulated evidence of transgenerational inheritance epigenetic and symbiotic changes raises fundamental questions about the possible types, significance duration impacts on population, as well whether, under which conditions, non‐genetic confers long‐term advantage to population. To address these questions, a population epigenetics model individuals undergoing stochastic and/or induced responses that are transmitted offspringis introduced. Potentially adaptive maladaptive represented, respectively, by environmentally driven reduce increase selective pressure. Analytic solutions in simplified case populations exposed either periodic or progressively deteriorating environments shows acquisition transmission alleviate pressure confer may facilitate escape from extinction. Systematic analysis outcomes function properties further identifies non‐traditional regime adaptation mediated rapidly acquired within lifetime. Contrasting predictions with experimental findings dynamically enables rapid unforeseen challenges can account for dynamics is unexpected beyond scope traditional models.

Language: Английский

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The epipliancy journey: Tumor initiation at the mercy of identity crisis and epigenetic drift

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2025, Volume and Issue: 1880(3), P. 189307 - 189307

Published: April 2, 2025

Cellular pliancy refers to the unique disposition of different stages cellular differentiation transform when exposed specific oncogenic insults. This concept highlights a strong interconnection between identity and tumorigenesis, implies overcoming epigenetic barriers defining states. Emerging evidence suggests that cell-type-specific response intrinsic extrinsic stresses is modulated by accessibility certain areas genome. Understanding interplay mechanisms, differentiation, insults crucial for deciphering complex nature tumorigenesis developing targeted therapies. Hence, relies on dynamic cooperation context through control, including reactivation such as epithelial-to-mesenchymal transition (EMT). Such mechanisms pathways confer plasticity cell allowing it adapt hostile environment in tumor initiation, thus changing its identity. Indeed, growing cancer disease crisis, whereby differentiated cells lose their defined gain progenitor characteristics. The loss fate commitment central feature appears be prerequisite neoplastic transformation. In this context, EMT-inducing transcription factors (EMT-TFs) cooperate with mitogenic oncoproteins foster malignant aberrant activation EMT-TFs plays an active role initiation alleviating key oncosuppressive endowing stem cell-like properties, ability self-renew, course tumorigenesis. highly phenotypic change occurs concomitantly major epigenome reorganization, component regulation. was initially proposed address fundamental question biology: why are some more likely become cancerous events at particular developmental stages? We propose epipliancy, difference configuration leads transformation following insult. Here, we present recent studies furthering our understanding how landscape may impact modulation during early initiation.

Language: Английский

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