Reprogramming of cancer-associated fibroblasts combined with immune checkpoint inhibitors: A potential therapeutic strategy for cancers

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2023, Volume and Issue: 1878(5), P. 188945 - 188945

Published: June 24, 2023

Language: Английский

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Clinical, histopathological and molecular features of dedifferentiated melanomas: An EORTC Melanoma Group Retrospective Analysis

European Journal of Cancer, Journal Year: 2023, Volume and Issue: 187, P. 7 - 14

Published: April 2, 2023

Dedifferentiated melanoma (DedM) poses significant diagnostic challenges. We aimed to investigate the clinical, histopathological and molecular features of DedM. Methylation signature (MS) copy number profiling (CNP) were carried out in a subgroup cases.A retrospective series 78 DedM tissue samples from 61 patients retrieved EORTC (European Organisation for Research Treatment Cancer) Melanoma Group centres centrally reviewed. Clinical retrieved. In patients, genotyping through Infinium microarray CNP analysis was out.Most (60/61) had metastatic showing most frequently an unclassified pleomorphic, spindle cell, or small round cell morphology akin undifferentiated soft sarcoma, rarely associated with heterologous elements. Overall, among 20 successfully analysed 16 we found retained melanoma-like MS only 7 while non-melanoma-like observed 13 samples. two whom multiple specimens analysed, some preserved cutaneous other exhibited epigenetic shift towards mesenchymal/sarcoma-like profile, matching histological features. these largely identical across all specimens, line their common clonal origin, despite modification epigenome.Our study further highlights that represents real challenge. While genomic may help pathologists diagnose DedM, provide proof-of-concept dedifferentiation is modifications.

Language: Английский

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Stromal Expression Profiling Reveals Immune‐Driven Adaption to Malignancy in Canine Melanoma Subtypes

Veterinary and Comparative Oncology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 17, 2024

Canine mucosal melanoma (CMM) is the most common oral malignancy in dogs and significantly more aggressive than its cutaneous counterpart (CCM), yet reasons for this disparity remain unclear. Cancer-associated stroma (CAS) plays a crucial role tumour progression, but detailed understanding of CAS canine missing. To assess stromal reprogramming, we analysed from 21 CMM, 14 CCM normal 10 skin 9 mucosa samples by laser-capture microdissection followed RNA sequencing. Results were assessed relation to subtypes, prognostic factors including mitotic count (MC), ulceration, necrosis, pigmentation immune cell infiltration (CD3, CD20 CD68), scored using immunohistochemistry situ hybridisation. Stromal reprogramming was evident both subtypes pronounced CMM. Immune-excluded tumours exhibited higher MC desert/cold ones. strongly correlated with genes associated B-cells, T-helper cells CTLA4 CCM, suggesting depend on malignancy. Finally, identify an immune-suppressive signature subset CMM characterised downregulation key checkpoints pathways. Together, these findings provide solid foundation melanoma, specific subtypes.

Language: Английский

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Current Status and Molecular Mechanisms of Resistance to Immunotherapy in Oral Malignant Melanoma

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(24), P. 17282 - 17282

Published: Dec. 8, 2023

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used various settings, first-line, adjuvant, neo-adjuvant therapy. In scope this review, we examined clinical studies utilizing context treating oral mucosal melanoma, rare disease, albeit with an extremely poor prognosis, specific focus on unraveling intricate web resistance mechanisms. The absence comprehensive review focusing melanoma is notable. Therefore, seeks to address deficiency by offering novel thorough analysis current status, potential mechanisms, future prospects applying specifically Clarifying thoroughly understanding these mechanisms will facilitate advancement effective therapeutic approaches enhance for patients suffering from

Language: Английский

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Extracellular matrix stiffness determines the phenotypic behavior of dedifferentiated melanoma cells through a DDR1/2-dependent YAP mechanotransduction pathway

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 27, 2024

Abstract Extracellular matrix (ECM) stiffening, resulting from increased collagen deposition and cross-linking, is a key biophysical factor of the tumor microenvironment. Cutaneous melanoma deadly metastatic cancer. Its aggressiveness stems high intratumoral heterogeneity, plasticity cells, which transit melanocytic state to dedifferentiated therapy-resistant invasive phenotypes, characterized by mesenchymal and/or neural crest stem cell-like features. Phenotypic regulated stroma-derived soluble factors, but functional impact ECM stiffening on cell phenotypes remains ill defined. Here, we found that subpopulations display difference in mechanical responsiveness. Compared cells showed proliferation, migration resistance MAP kinase-targeted therapy when seeded stiff collagen. By contrast, soft impaired their proliferation sensitized them targeted therapy. In addition, extracellular signals are required sustain identity dedifferentiation Further analyses indicated mechanosensitivity nature relies expression activation receptors DDR1 DDR2 control actomyosin cytoskeleton reorganization YAP mechanotransduction pathway. Inhibiting both DDR abrogated mechano-induced behavior drug-resistant phenotype, while forcing induced responsiveness less differentiated phenotype. Our results reveal phenotypic reprogramming endows with sensitivity addiction stiffness. We propose mechano-addiction mediated may represent novel vulnerability for aggressive cancer can be exploited therapeutic benefits.

Language: Английский

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Pre-Treatment DNA Methylome and Transcriptome Profiles Correlate with Melanoma Response to Anti-Pd1 Immunotherapy

Published: Jan. 1, 2024

Language: Английский

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B-Cells Extracellular Vesicles Shape Melanoma Response to Immune Checkpoint Therapy

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

ABSTRACT The immune tumor microenvironment (TME) is increasingly recognized as a dynamic ecosystem where B cells play pivotal roles in modulating therapeutic responses, particularly the context of checkpoint blockade (ICB) therapy. While have traditionally been viewed bystanders immunity, recent evidence suggests they may actively influence anti-tumor albeit with conflicting reports regarding their pro-tumor or roles. This study explores crucial played by and secreted extracellular vesicles (EVs) shaping melanoma responses to ICB We show significant enrichment therapy responders compared non-responders, pre-treatment, through retrospective analyses patient tumors. Functional assays demonstrate that cell depletion impairs T cell-mediated cytotoxicity, underscoring importance responses. To investigate clinical relevance, EVs were isolated from tumors, fractioned into subpopulations. MiRNA profiling CD19+ identifies miR-99a-5p top candidate, among several others, upregulated responders. silencing diminishes activity, suggesting its role promoting Mechanistically, influences maturation within TME mediating class-switch recombination. Our findings highlight important derived efficacy immunotherapy, paving way for novel strategies targeting cell-related pathways. Graphical abstract (created Biorender)

Language: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 10, 2023

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- inter-tumoral phenotypic heterogeneity, such as IFNγ signaling proliferative invasive transition, but how their crosstalk impacts tumor progression remains largely elusive. 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. 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 immune-suppression. This be aggravated combinatorial these regulators signaling. changes evade inhibitors sets from vitro vivo experiments. 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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Characterization the prognosis role and effects of snoRNAs in melanoma patients

Experimental Dermatology, Journal Year: 2023, Volume and Issue: 33(1)

Published: Sept. 29, 2023

Abstract Melanoma is a melanocyte‐derived malignant cancer and known for its early metastasis high mortality rates. It highly cutaneous tumour disease that could be related to the abnormal immune microenvironment, identification of reliable diagnostic prognostic markers crucial improving patient outcomes. In search biomarkers, various types RNAs have been discovered recognized as markers. Among these, small nucleolar (snoRNAs) emerged promising avenue studying diagnosis in tumours due their widespread presence tissues, specificity stability. our study, we analysed snoRNAs data from melanoma samples TCGA‐SKCM cohort developed model comprising 12 (SNORD9, SNORA31, SNORD14E, SNORA14A, SNORA5A, SNORD83A, SNORA75, AL096855, AC007684, SNORD14A, SNORA65 AC004839). This exhibited unique accuracy demonstrated significant correlation with infiltration microenvironment. Additionally, analysis GSE213145 dataset, which explored sensitivity resistance checkpoint inhibitors, further supported potential immunotherapy. Overall, study contributes immune‐related biomarkers patients. These findings can offer valuable insights future discovery novel treatment strategies hold promise clinical outcomes

Language: Английский

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Tunable PhenoCycler Imaging of the Murine Pre-Clinical Tumour Microenvironments

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 22, 2023

Abstract The tumour microenvironment (TME) consists of tumour-supportive immune cells, endothelial and fibroblasts. PhenoCycler, a high-plex single cell imaging platform, is used to characterize the complexity TME. Here, we PhenoCycler spatially resolve TME 8 routinely employed pre-clinical models lymphoma, breast cancer, melanoma. Our data reveal distinct TMEs in different cancer that were imaged, show cell-cell contacts differ depending on type examined. For instance, found infiltration murine model melanoma altered cellular organization melanomas become resistant αPD-1 therapy, with depletions number interactions. Furthermore, provide detailed pipelines for conjugation antibodies are optimized staining FFPE tissues specifically, alongside open-source analysis procedures. Overall, this valuable resource study seamlessly adaptable any field research involving models.

Language: Английский

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