Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies DOI Creative Commons
Jun He,

Zejing Qiu,

Jingjing Fan

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 14, 2024

Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance. Among these, the tolerant persister (DTP) cell phenotype is attracting more and attention giving a predominant non-genetic role in cancer therapy The DTP characterized by quiescent or slow-cell-cycle reversible state subpopulation inert specialization to stimuli, which tolerates exposure some extent through interaction multiple underlying recovering growth proliferation after withdrawal, ultimately leading treatment resistance recurrence. Therefore, targeting cells anticipated provide new opportunities for patients, although our current knowledge these remains limited. In this review, we comprehensive overview formation characteristics cells, investigate potential drugs (including preclinical drugs, novel use old natural products) based on different medicine models, discuss necessity feasibility anti-DTP therapy, related application forms, future issues that will need be addressed advance emerging field towards clinical applications. Nonetheless, understanding functions may enable us develop effective improve outcomes patients.

Language: Английский

Circulating tumor cells: from new biological insights to clinical practice DOI Creative Commons
Xuyu Gu, Shiyou Wei,

Xin Lv

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Sept. 2, 2024

Abstract The primary reason for high mortality rates among cancer patients is metastasis, where tumor cells migrate through the bloodstream from original site to other parts of body. Recent advancements in technology have significantly enhanced our comprehension mechanisms behind bloodborne spread circulating (CTCs). One critical process, DNA methylation, regulates gene expression and chromosome stability, thus maintaining dynamic equilibrium Global hypomethylation locus-specific hypermethylation are examples changes methylation patterns that pivotal carcinogenesis. This comprehensive review first provides an overview various processes contribute formation CTCs, including epithelial-mesenchymal transition (EMT), immune surveillance, colonization. We then conduct in-depth analysis how modifications within CTCs impact each these stages during CTC dissemination. Furthermore, we explored potential clinical implications with cancer. By understanding epigenetic modifications, can gain insights into metastatic process identify new biomarkers early detection, prognosis, targeted therapies. aims bridge gap between basic research application, highlighting significance context metastasis offering avenues improving patient outcomes.

Language: Английский

Citations

29
Revealing microRNA regulation in single cells DOI Creative Commons
Ranjan Kumar Maji, Matthias S. Leisegang, Reinier A. Boon

et al.

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

Published: Jan. 1, 2025

MicroRNAs (miRNAs) are key regulators of gene expression and control cellular functions in physiological pathophysiological states. miRNAs play important roles disease, stress, development, now being investigated for therapeutic approaches. Alternative processing during biogenesis results the generation miRNA isoforms (isomiRs) which further diversify regulation. Single-cell RNA-sequencing (scsRNA-seq) technologies, together with computational strategies, enable exploration miRNAs, isomiRs, interacting RNAs at level. By integration other miRNA-associated single-cell modalities, can be resolved different stages In this review we discuss (i) experimental assays that measure isomiR abundances, (ii) methods their analysis to investigate mechanisms post-transcriptional

Language: Английский

Citations

3
Hybrid EMT Phenotype and Cell Membrane Tension Promote Colorectal Cancer Resistance to Ferroptosis DOI Creative Commons
Xiaowei Wei, Yutong Ge,

Yaolin Zheng

et al.

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

Published: Feb. 22, 2025

Abstract Intratumoral heterogeneity, including epithelial–mesenchymal transition (EMT), is one major cause of therapeutic resistance. The induction ferroptosis, an iron‐dependent death, has the potential in overcoming this resistance to traditional treatment modalities. However, roles distinct EMT phenotypes ferroptosis remain enigma. This study reports that 3D soft fibrin microenvironment confers colorectal cancer (CRC) cells hybrid phenotype and high level ferroptosis. activation histone acetylation WNT/β‐catenin signaling drives phenotypic transition, which promotes defense CRCs against via glutathione peroxidases/ferritin axis. Unexpectedly, E‐cadherin knockout but not 2D mediates integrin β 3 marked‐late state further enhances integrin‐mediated tension mitochondrial reprogramming. inhibition α v ‐mediated WNT/β‐catenin‐mediated sensitizes with without deficiency vivo, respectively. Further, patient‐derived tumoroids associated CRC In summary, uncovers previously unappreciated cell membrane only predict efficacy also potentiate development new ferroptosis‐based targeted strategies.

Language: Английский

Citations

3
Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis DOI Creative Commons
Goodwin G. Jinesh, Andrew S. Brohl

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 23, 2022

Abstract Metastasis is a pivotal event that accelerates the prognosis of cancer patients towards mortality. Therapies aim to induce cell death in metastatic cells require more detailed understanding metastasis for better mitigation. Towards this goal, we discuss details two distinct but overlapping pathways metastasis: classical reversible epithelial-to-mesenchymal transition (hybrid-EMT)-driven transport pathway and an alternative process-driven blebbishield metastatic-witch (BMW) involving process. The knowledge about EMT BMW important therapy cancers as these confer drug resistance coupled immune evasion/suppression. We initially compare it with contexts coordinated oncogenic, metabolic, immunologic, biological events drive metastasis. In particular, how environment apoptosis, ferroptosis, necroptosis, NETosis or recruits cells, fuses it, migrates, permeabilizes vasculature, settles at distant sites establish Finally, therapeutic targets are common both pathways.

Language: Английский

Citations

61
Landscape of epithelial–mesenchymal plasticity as an emergent property of coordinated teams in regulatory networks DOI Creative Commons
Kishore Hari,

Varun Ullanat,

Archana Balasubramanian

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Oct. 21, 2022

Elucidating the design principles of regulatory networks driving cellular decision-making has fundamental implications in mapping and eventually controlling cell-fate decisions. Despite being complex, these often only give rise to a few phenotypes. Previously, we identified two 'teams' nodes small cell lung cancer network that constrained phenotypic repertoire aligned strongly with dominant phenotypes obtained from simulations (Chauhan et al., 2021). However, it remained elusive whether exist other networks, how do they shape landscape. Here, demonstrate five different varying sizes governing epithelial-mesenchymal plasticity comprised players - one canonical drivers epithelial phenotype containing mesenchymal inducers. These are specific topology orchestrate bimodal landscape more frequent dynamically robust perturbations, relative intermediary/hybrid epithelial/mesenchymal ones. Our analysis reveals alone can contain information about corresponding distributions, thus obviating need simulate them. We propose as principle drive canalization diverse processes.

Language: Английский

Citations

53
Epithelial–Mesenchymal Plasticity in Tumor Immune Evasion DOI Open Access
Riley Mullins, Ananya Pal, Thomas F. Barrett

et al.

Cancer Research, Journal Year: 2022, Volume and Issue: 82(13), P. 2329 - 2343

Published: April 1, 2022

Epithelial-mesenchymal transition (EMT) is a fundamental process that occurs during embryogenesis and tissue repair. However, EMT can be hijacked by malignant cells, where it may promote immune evasion metastasis. Classically considered dichotomous transition, in cancer has recently been plastic whereby cells display interconvert among hybrid epithelial/mesenchymal (E/M) states. plasticity (EMP) associated E/M states are divergent from classical EMT, with unique immunomodulatory effects. Here, we review recent insights into the EMP-immune cross-talk, highlighting possible mechanisms of conferred roles EMP.

Language: Английский

Citations

40
The Significance of Cancer Stem Cells and Epithelial–Mesenchymal Transition in Metastasis and Anti-Cancer Therapy DOI Open Access
Lili Liang, Andreas M. Kaufmann

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2555 - 2555

Published: Jan. 29, 2023

Cancer stem cells (CSCs) have been identified and characterized in both hematopoietic solid tumors. Their existence was first predicted by Virchow Cohnheim the 1870s. Later, many studies showed that CSCs can be isolated their expression of specific cell markers. The significance with respect to tumor biology anti-cancer treatment lies ability maintain quiescence very slow proliferation, indefinite self-renewal, differentiation, trans-differentiation such as epithelial-mesenchymal transition (EMT) its reverse process mesenchymal-epithelial (MET). for detachment, migration, extra- intravasation, invasion thereby completing all necessary steps metastatic cascade highlights metastasis. comprise cancer populations responsible growth, resistance therapies In this review, history CSC theory, identification characterization are described. contribution undergo EMT metastasis is discussed. Recently, novel strategies drug development focused on elimination specifically. unique functional molecular properties discussed possible therapeutic vulnerabilities anti-metastasis treatments. Prospectively, may provide precise personalized treatments improved efficiency fewer side effects leading better prognosis.

Language: Английский

Citations

34
Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy DOI Creative Commons
Yuanzhuo Gu, Zhengkui Zhang, Peter ten Dijke

et al.

Cellular and Molecular Immunology, Journal Year: 2023, Volume and Issue: 20(4), P. 318 - 340

Published: Feb. 24, 2023

Abstract Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, most patients fail to respond or achieve durable responses due primary acquired ICB resistance. Recently, tumor epithelial-to-mesenchymal plasticity (EMP) was identified as critical determinant in regulating immune escape and immunotherapy resistance cancer. In this review, we summarize the emerging role of EMP tumor-intrinsic extrinsic mechanisms by which tumors exploit immunosuppression escape. We discuss strategies modulate alleviate enhance efficiency therapy. Our discussion provides new prospects response therapeutic gain patients.

Language: Английский

Citations

31
The ELF3 transcription factor is associated with an epithelial phenotype and represses epithelial-mesenchymal transition DOI Creative Commons

Ayalur Raghu Subbalakshmi,

Sarthak Sahoo,

Prakruthi Manjunatha

et al.

Journal of Biological Engineering, Journal Year: 2023, Volume and Issue: 17(1)

Published: March 2, 2023

Epithelial-mesenchymal plasticity (EMP) involves bidirectional transitions between epithelial, mesenchymal and multiple intermediary hybrid epithelial/mesenchymal phenotypes. While the process of epithelial-mesenchymal transition (EMT) its associated transcription factors are well-characterised, that promote mesenchymal-epithelial (MET) stabilise E/M phenotypes less well understood.Here, we analyse publicly-available transcriptomic datasets at bulk single-cell level pinpoint ELF3 as a factor is strongly with an epithelial phenotype inhibited during EMT. Using mechanism-based mathematical modelling, also show inhibits progression This behaviour was observed in presence EMT inducing WT1. Our model predicts MET induction capacity stronger than KLF4, but weaker GRHL2. Finally, levels correlates worse patient survival subset solid tumour types.ELF3 shown to be found inhibit complete suggesting may able counteract induction, including EMT-inducing factors, such The analysis data indicates prognostic specific cell-of-origin or lineage.

Language: Английский

Citations

26
Proactive and reactive roles of TGF-β in cancer DOI Creative Commons
Nick A. Kuburich,

Thiru Sabapathy,

Breanna R. Demestichas

et al.

Seminars in Cancer Biology, Journal Year: 2023, Volume and Issue: 95, P. 120 - 139

Published: Aug. 10, 2023

Cancer cells adapt to varying stress conditions survive through plasticity. Stem exhibit a high degree of plasticity, allowing them generate more stem or differentiate into specialized cell types contribute tissue development, growth, and repair. can also plasticity acquire properties that enhance their survival. TGF-β is an unrivaled growth factor exploited by cancer gain TGF-β-mediated signaling enables carcinoma alter epithelial mesenchymal epithelial-mesenchymal (EMP). However, multifunctional cytokine; thus, the be detrimental beneficial depending on cellular context. Those overcome anti-tumor effect induce transition (EMT) EMP benefits. allows tumor immune microenvironment (TIME), facilitating Due significant roles in progression, it essential understand how exploit this This understanding will guide development effective TGF-β-targeting therapies eliminate

Language: Английский

Citations

23