Phenotype Switching and the Melanoma Microenvironment; Impact on Immunotherapy and Drug Resistance

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1601 - 1601

Published: Jan. 13, 2023

Melanoma, a highly heterogeneous tumor, is comprised of functionally diverse spectrum cell phenotypes and subpopulations, including stromal cells in the tumor microenvironment (TME). Melanoma has been shown to dynamically shift between different transcriptional states or phenotypes. This referred as phenotype switching melanoma, it involves quiescent proliferative cycle states, dramatic shifts invasiveness, well changes signaling pathways melanoma cells, immune composition TME. plasticity associated with altered gene expression cancer-associated fibroblasts, extracellular matrix, which drive metastatic cascade therapeutic resistance. Therefore, resistance therapy not only dependent on genetic evolution, but also suggested be driven by adaptive phenotypic plasticity. review discusses recent findings switching, immunotherapy resistance, balancing homeostatic TME subpopulations. We discuss future perspectives biology neural crest-like state(s) melanoma.

Language: Английский

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The mechanical phenotypic plasticity of melanoma cell: an emerging driver of therapy cross-resistance

Oncogenesis, Journal Year: 2023, Volume and Issue: 12(1)

Published: Feb. 11, 2023

Abstract Advanced cutaneous melanoma is the deadliest form of skin cancer and one most aggressive human cancers. Targeted therapies (TT) against BRAF mutated immune checkpoints blockade (ICB) have been a breakthrough in treatment metastatic melanoma. However, therapy-driven resistance remains major hurdle clinical management disease. Besides shaping tumor microenvironment, current treatments impact transition states to promote cell phenotypic plasticity intratumor heterogeneity, which compromise efficacy outcomes. In this context, mesenchymal-like dedifferentiated cells exhibit remarkable ability autonomously assemble their own extracellular matrix (ECM) biomechanically adapt response therapeutic insults, thereby fueling relapse. Here, we review recent studies that highlight mechanical as hallmark adaptive non-genetic emerging driver cross-resistance TT ICB. We also discuss how targeting BRAF-mutant ECM-based mechanotransduction pathways may overcome cross-resistance.

Language: Английский

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Genomic and Epigenomic Biomarkers of Immune Checkpoint Immunotherapy Response in Melanoma: Current and Future Perspectives

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7252 - 7252

Published: June 30, 2024

Immune checkpoint inhibitors (ICIs) demonstrate durable responses, long-term survival benefits, and improved outcomes in cancer patients compared to chemotherapy. However, the majority of do not respond ICIs, a high proportion those who ICI therapy develop innate or acquired resistance limiting their clinical utility. The most studied predictive tissue biomarkers for response are PD-L1 immunohistochemical expression, DNA mismatch repair deficiency, tumour mutation burden, although these weak predictors response. identification better remains an important goal improve would benefit from ICIs. Here, we review established emerging response, focusing on epigenomic genomic alterations patients, which have potential help guide single-agent immunotherapy combination with other immunotherapies agents. We briefly current status biomarkers, including investigational present insights into several promising biomarker candidates, knowledge gaps context melanoma patients.

Language: Английский

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Interferon-stimulated gene IFI27 as a multifaceted candidate target in precision medicine

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

Published: March 1, 2025

IFI27, an interferon (IFN)-stimulated gene, is emerging as a crucial player in immune responses across various species, with significant implications for precision medicine. Commonly found among the most upregulated genes infections, cancers, well inflammatory and autoimmune disorders, IFI27 ready to be trialed clinical practice certain indications, holds promise immunomodulatory target. We hypothesize that plays dual role, typically supporting defense but sometimes contributing disease progression, which might render it putative biomarker diagnosis, prognosis, treatment response. advocate focused research on unlock its potential medicine contribute unifying framework of mechanisms Our viewpoint supported by numerous studies highlighting IFI27's involvement conditions possibilities application.

Language: Английский

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Pre-treatment DNA methylome and transcriptome profiles correlate with melanoma response to anti-PD1 immunotherapy

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217638 - 217638

Published: March 1, 2025

Language: Английский

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Dynamical modeling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(9), P. e006766 - e006766

Published: Sept. 1, 2023

Background Phenotypic heterogeneity of melanoma cells contributes to drug tolerance, increased metastasis, and immune evasion in patients with progressive disease. Diverse mechanisms have been individually reported shape extensive intra-tumor inter-tumor phenotypic heterogeneity, such as IFNγ signaling proliferative invasive transition, but how their crosstalk impacts tumor progression remains largely elusive. Methods Here, we integrate dynamical systems modeling transcriptomic data analysis at bulk single-cell levels investigate underlying behind its impact on adaptation targeted therapy checkpoint inhibitors. We construct a minimal core regulatory network involving transcription factors implicated this process identify the multiple ‘attractors’ landscape enabled by network. Our model predictions about synergistic control PD-L1 transition were validated experimentally three cell lines—MALME3, SK-MEL-5 A375. Results demonstrate that emergent dynamics our comprising MITF, SOX10, SOX9, JUN ZEB1 can recapitulate experimental observations co-existence diverse phenotypes (proliferative, neural crest-like, invasive) reversible cell-state transitions among them, including response These varied PD-L1, driving immunosuppression. This be aggravated combinatorial these regulators signaling. changes evade inhibitors RNA-seq sets from vitro vivo experiments. Conclusion calibrated offers platform test therapies provide rational avenues for treatment metastatic melanoma. improved understanding expression, leveraged improve clinical management therapy-resistant

Language: Английский

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Tunable PhenoCycler imaging of the murine pre-clinical tumour microenvironments

Cell & Bioscience, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 4, 2024

The tumour microenvironment (TME) consists of tumour-supportive immune cells, endothelial and fibroblasts. PhenoCycler, a high-plex single cell spatial biology imaging platform, is used to characterize the complexity TME. Researchers worldwide harvest bank tissues from mouse models which are employed model plethora human disease. With explosion interest in biology, these panoplies archival provide valuable resource answer new questions. Here, we describe our protocols for developing tunable PhenoCycler multiplexed panels open-source data analysis pipeline. Using protocols, spatially resolve TME 8 routinely pre-clinical lymphoma, breast cancer, melanoma preserved as FFPE.

Language: Английский

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Glyco-signatures in patients with advanced lung cancer during anti-PD-1/PD-L1 immunotherapy

Acta Biochimica et Biophysica Sinica, Journal Year: 2024, Volume and Issue: 56(8), P. 1099 - 1107

Published: June 1, 2024

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1/programmed ligand-1 (PD-1/PD-L1) have significantly prolonged the survival of advanced/metastatic patients with lung cancer. However, only a small proportion can benefit from ICIs, and clinical management treatment process remains challenging. Glycosylation has added new dimension to advance our understanding tumor immunity immunotherapy. To systematically characterize anti-PD-1/PD-L1 immunotherapy-related changes in serum glycoproteins, series samples 12 metastatic squamous carcinoma (SCC) adenocarcinoma (ADC), collected before during ICIs treatment, are firstly analyzed mass-spectrometry-based label-free quantification method. Second, stratification analysis is performed among responders non-responders, levels glycopeptides correlated response. In addition, an independent validation cohort, large-scale site-specific profiling strategy based on chemical labeling employed confirm unusual characteristics IgG N-glycosylation associated treatment. Unbiased quantitative glycoproteomics reveals levels' alterations related 27 out 337 quantified glycopeptides. The intact glycopeptide EEQFN

Language: Английский

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The CD73 is induced by TGF-β1 triggered by nutrient deprivation and highly expressed in dedifferentiated human melanoma

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 165, P. 115225 - 115225

Published: July 29, 2023

CD73 is the key enzyme in generation of extracellular adenosine, a mediator involved tumor progression, immune escape and resistance to anti-cancer therapeutics. Microenvironmental conditions influence expression cells. However how activity regulated stress condition lower nutrient availability are largely unknown. Our results indicate that serum starvation leads marked up-regulation on A375 melanoma cells time-dependent manner. The cell-surface associated with an increased release TGF-β1 by starved Blockade receptors or TGFβ/SMAD3 signaling pathway significantly reduce induced starvation. Treatment rTGF-β1 up-regulates concentration-dependent manner, confirming role this regulating enhanced AMPase activity, which selectively reduced inhibitors APCP PSB-12489. Pharmacological blockade inhibits invasion transwell system. Furthermore, using multiplex immunofluorescence imaging we found that, within human metastases, at dedifferentiated stage show highest protein expression. In summary, our data provide new insights into mechanism expression/activity nutrients, common feature microenvironment. Within metastatic tissues elevated invasive-like phenotype.

Language: Английский

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Immune Checkpoint Inhibitor Therapy for Metastatic Melanoma: What Should We Focus on to Improve the Clinical Outcomes?

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 10120 - 10120

Published: Sept. 20, 2024

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma. However, over 50% of patients experience limited or no response to ICI therapy. Resistance ICIs is influenced a complex interplay tumour intrinsic and extrinsic factors. This review summarizes current for melanoma the factors involved resistance treatment. We also discuss emerging evidence that microbiota can impact outcomes modulating biology function. Furthermore, profiles may offer non-invasive method predicting response. Therefore, future research into manipulation could provide cost-effective strategies enhance improve patients.

Language: Английский

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