Persister state-directed transitioning and vulnerability in melanoma DOI Creative Commons
Heike Chauvistré,

Batool Shannan,

Sheena M. Daignault-Mill

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: June 1, 2022

Abstract Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. cells with high expression H3K4 demethylase KDM5B (JARID1B) rest in slow-cycling, yet reversible persister state. Over time, can promote rapid repopulation equilibrated heterogeneity. The cellular identity has not been studied so far, missing an important state-directed treatment opportunity melanoma. Here, we have established doxycycline-titratable system for genetic induction permanent intratumor and screened chemical agents that phenocopy this effect. Transcriptional profiling functional assays confirmed dihydropyridine 2-phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports directs melanoma towards differentiation along melanocytic lineage to cycle-arrest. state additionally prevents proliferation through negative regulation cytokinetic abscission. Moreover, Cpd1 promoted melanocyte-specific tyrosinase gene specifically sensitizing tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(–)-epicatechin (TMECG). In summary, our study provides proof-of-concept dual hit strategy melanoma, which transitioning limits plasticity primes lineage-specific elimination.

Language: Английский

Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance DOI Creative Commons
Khalil Khalaf,

Doris Hana,

Jadzia Tin-Tsen Chou

et al.

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: May 27, 2021

The tumor microenvironment (TME) is a complex and ever-changing “rogue organ” composed of its own blood supply, lymphatic nervous systems, stroma, immune cells extracellular matrix (ECM). These components, utilizing both benign malignant cells, nurture the harsh, immunosuppressive nutrient-deficient environment necessary for cell growth, proliferation phenotypic flexibility variation. An important aspect TME cellular crosstalk cell-to-ECM communication. This interaction induces release soluble factors responsible evasion ECM remodeling, which further contribute to therapy resistance. Other aspects are presence exosomes contributed by circulating deregulated microRNAs TME-specific metabolic patterns potentiate progression and/or resistance therapy. In addition biochemical signaling, specific characteristics such as hypoxic environment, derangements, abnormal mechanical forces have been implicated in development treatment this review, we will provide an overview microenvironmental composition, structure, features that influence suppression

Language: Английский

Citations

315
Metabolic reprogramming in cancer: Mechanisms and therapeutics DOI Creative Commons

Shiqi Nong,

Xiaoyue Han, Xiang Yu

et al.

MedComm, Journal Year: 2023, Volume and Issue: 4(2)

Published: March 27, 2023

Abstract Cancer cells characterized by uncontrolled growth and proliferation require altered metabolic processes to maintain this characteristic. Metabolic reprogramming is a process mediated various factors, including oncogenes, tumor suppressor genes, changes in tumor–host cell interactions, which help meet the needs of cancer anabolism promote development. dynamically variable, depending on type microenvironment, involves multiple pathways. These pathways have complex mechanisms involve coordination signaling molecules, proteins, enzymes, increases resistance traditional antitumor therapies. With development therapies, has been recognized as new therapeutic target for cells. Therefore, understanding how change can provide reference therapies treatment. Here, we systemically reviewed their alteration together with current regulation treatments other possible that are still under investigation. Continuous efforts needed further explore mechanism metabolism corresponding treatments.

Language: Английский

Citations

100
Drug-Tolerant Persister Cells in Cancer Therapy Resistance DOI Open Access

Pavan Kumar Dhanyamraju,

Todd D. Schell, Shantu Amin

et al.

Cancer Research, Journal Year: 2022, Volume and Issue: 82(14), P. 2503 - 2514

Published: May 18, 2022

One of the current stumbling blocks in our fight against cancer is development acquired resistance to therapy, which attributable approximately 90% cancer-related deaths. Undercutting this process during treatment could significantly improve management. In many cases, drug mediated by a drug-tolerant persister (DTP) cell subpopulation present tumors, often referred as cells. This review provides summary currently known subpopulations and approaches target them. A specific DTP with elevated levels aldehyde dehydrogenase (ALDH) activity has stem cell-like characteristics high level plasticity, enabling them switch rapidly between low ALDH activity. Further studies are required fully elucidate functions ALDH-high cells, how they withstand concentrations that kill other adapt under cellular stress eventually lead more aggressive, recurrent, drug-resistant cancer. Furthermore, addresses processes used enable progression, isoforms important these processes, interactions DTPs tumor microenvironment, therapeutically modulate order effectively manage

Language: Английский

Citations

74
Drug-tolerant persister cells in cancer: the cutting edges and future directions DOI
Yi Pu, Lu Li, Haoning Peng

et al.

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 20(11), P. 799 - 813

Published: Sept. 25, 2023

Language: Английский

Citations

65
Lipid Metabolism and Resistance to Anticancer Treatment DOI Creative Commons
Nicolas Germain,

Mélanie Dhayer,

M. Boileau

et al.

Biology, Journal Year: 2020, Volume and Issue: 9(12), P. 474 - 474

Published: Dec. 16, 2020

Metabolic reprogramming is crucial to respond cancer cell requirements during tumor development. In the last decade, metabolic alterations have been shown modulate cells’ sensitivity chemotherapeutic agents including conventional and targeted therapies. Recently, it became apparent that changes in lipid metabolism represent important mediators of resistance anticancer agents. this review, we highlight associated with therapy resistance, their significance how dysregulated could be exploited overcome drug resistance.

Language: Английский

Citations

91
Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells DOI Open Access
Giulia De Conti, Matheus Henrique Dias, René Bernards

et al.

Cancers, Journal Year: 2021, Volume and Issue: 13(5), P. 1118 - 1118

Published: March 5, 2021

Designing specific therapies for drug-resistant cancers is arguably the ultimate challenge in cancer therapy. While much emphasis has been put on study of genetic alterations that give rise to drug resistance, less known about non-genetic adaptation mechanisms operate during early stages resistance development. Drug-tolerant persister cells have suggested be key players this process. These are thought undergone adaptations enable survival presence a drug, from which full-blown resistant may emerge. Such initial often involve engagement stress response programs maintain cell viability. In review, we discuss nature drug-tolerant phenotypes, as well involved. We also how malignant employ homeostatic pathways mitigate intrinsic costs such adaptations. Lastly, vulnerabilities introduced by these and might exploited therapeutically.

Language: Английский

Citations

72
The peroxisome: an up-and-coming organelle in immunometabolism DOI
Francesca Di Cara, Stéphane Savary, Werner J. Kovacs

et al.

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 33(1), P. 70 - 86

Published: July 1, 2022

Language: Английский

Citations

65
PINK1-Mediated Mitophagy Promotes Oxidative Phosphorylation and Redox Homeostasis to Induce Drug-Tolerant Persister Cancer Cells DOI Open Access
Yun Li, Hengxing Chen, Xuan Xie

et al.

Cancer Research, Journal Year: 2022, Volume and Issue: 83(3), P. 398 - 413

Published: Dec. 8, 2022

The drug-tolerant persister (DTP) state enables cancer cells to evade cytotoxic stress from anticancer therapy. However, the mechanisms governing DTP generation remain poorly understood. Here, we observed that lung adenocarcinoma (LUAD) and organoids entered a quiescent survive MAPK inhibitor treatment. following inhibition underwent metabolic switch glycolysis oxidative phosphorylation (OXPHOS). PTEN-induced kinase 1 (PINK1), serine/threonine initiates mitophagy, was upregulated maintain mitochondrial homeostasis during generation. PINK1-mediated mitophagy supported cell survival contributed poor prognosis. Mechanistically, pathway resulted in MYC-dependent transcriptional upregulation of PINK1, leading activation. Mitophagy using either clinically applicable chloroquine or depletion PINK1 eradicated drug tolerance allowed complete response inhibitors. This study uncovers as novel tumor protective mechanism for generation, providing therapeutic opportunity eradicate achieve responses.DTP cause relapse after therapy critically depend on reprogramming, prolong treatment efficacy.

Language: Английский

Citations

59
Mitochondrial and metabolic alterations in cancer cells DOI Creative Commons
Jacopo Di Gregorio, Sabrina Petricca, Roberto Iorio

et al.

European Journal of Cell Biology, Journal Year: 2022, Volume and Issue: 101(3), P. 151225 - 151225

Published: April 13, 2022

Metabolic alterations have been observed in many cancer types. The deregulated metabolism has thus become an emerging hallmark of the disease, where is frequently rewired to aerobic glycolysis. This led concept "metabolic reprogramming", which therefore extensively studied. Over years, it characterized enhancement glycolysis, key mutations some enzymes TCA cycle, and increased glucose uptake, are used by cells achieve a phenotype" useful gain proliferation advantage. Many studies highlighted detail signaling pathways molecular mechanisms responsible for glycolytic switch. However, glycolysis not only metabolic process that rely on. Oxidative Phosphorylation (OXPHOS), gluconeogenesis or beta-oxidation fatty acids (FAO) may be involved development progression several tumors. In cases, these metabolisms even more crucial than tumor survival. review will focus on contribution survival cancers. We also analyze balance between processes regulated, as well therapeutical approaches can derive from their study.

Language: Английский

Citations

45
Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse DOI Creative Commons
Meng Nie, Na Chen, Huanhuan Pang

et al.

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(20)

Published: Sept. 1, 2022

Although first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is effective for treating EGFR-mutant non–small cell lung cancer (NSCLC), it now understood that drug-tolerant persister (DTP) cells escaping from initial treatment eventually drives drug resistance. Here, through integration of metabolomics and transcriptomics, we found the neurotransmitter acetylcholine (ACh) was specifically accumulated in DTP cells, demonstrated with EGFR-TKI heightened expression rate-limiting enzyme choline acetyltransferase (ChAT) ACh biosynthesis via YAP mediation. Genetic pharmacological manipulation or signaling could predictably regulate extent formation vitro vivo. Strikingly, pharmacologically targeting ACh/M3R an FDA-approved drug, darifenacin, retarded tumor relapse Mechanistically, upregulated metabolism mediated tolerance part activating WNT muscarinic 3 (M3R). Importantly, showed aberrant patients NSCLC played a potential role predicting response rate progression-free survival. Our study therefore defines therapeutic strategy — ACh/M3R/WNT axis manipulating EGFR TKI NSCLC.

Language: Английский

Citations

41