The Single‐Cell Landscape of Intratumoral Heterogeneity and The Immunosuppressive Microenvironment in Liver and Brain Metastases of Breast Cancer

Advanced Science, Journal Year: 2022, Volume and Issue: 10(5)

Published: Dec. 18, 2022

Distant metastasis remains the major cause of morbidity for breast cancer. Individuals with liver or brain have an extremely poor prognosis and low response rates to anti-PD-1/L1 immune checkpoint therapy compared those at other sites. Therefore, it is urgent investigate underlying mechanism resistance develop more effective immunotherapy strategies these patients. Using single-cell RNA sequencing, a high-resolution map entire tumor ecosystem based on 44 473 cells from cancer metastases depicted. Identified by canonical markers confirmed multiplex immunofluorescent staining, metastatic features remarkable reprogramming immunosuppressive such as FOXP3+ regulatory T cells, LAMP3+ tolerogenic dendritic CCL18+ M2-like macrophages, RGS5+ cancer-associated fibroblasts, LGALS1+ microglial cells. In addition, PD-1 PD-L1/2 are barely expressed in CD8+ cancer/immune/stromal respectively. Interactions molecules LAG3-LGALS3 TIGIT-NECTIN2 between found play dominant roles escape. summary, this study dissects intratumoral heterogeneity microenvironment first time, providing insights into most appropriate

Language: Английский

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Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: June 8, 2023

Abstract Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary cancer treatment modality, offering long-lasting responses and survival benefits for substantial number of patients. However, response rates to ICIs vary significantly among individuals types, with notable proportion patients exhibiting resistance or showing no response. Therefore, dual ICI combination therapy has been proposed potential strategy address these challenges. One targets is TIGIT, an inhibitory receptor associated T-cell exhaustion. TIGIT diverse immunosuppressive effects on immunity cycle, including inhibition natural killer cell effector function, suppression dendritic maturation, promotion macrophage polarization M2 phenotype, differentiation T cells regulatory cells. Furthermore, linked PD-1 expression, it can synergize PD-1/PD-L1 blockade enhance tumor rejection. Preclinical studies demonstrated co-inhibition in enhancing anti-tumor improving outcomes several types. Several clinical trials are underway evaluate safety efficacy various results awaited. This review provides overview mechanisms treatment, summarizes latest investigating this therapy, discusses its prospects. Overall, represents promising therapeutic approach that improve treated ICIs.

Language: Английский

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Methylation of GPRC5A promotes liver metastasis and docetaxel resistance through activating mTOR signaling pathway in triple negative breast cancer

Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 73, P. 101063 - 101063

Published: Feb. 1, 2024

This study aims to explore the function and mechanism of G Protein-coupled receptor class C group 5 member A (GPRC5A) in docetaxel-resistance liver metastasis breast cancer.

Language: Английский

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Lactate in the tumor microenvironment: A rising star for targeted tumor therapy

Frontiers in Nutrition, Journal Year: 2023, Volume and Issue: 10

Published: Feb. 16, 2023

Metabolic reprogramming is one of fourteen hallmarks tumor cells, among which aerobic glycolysis, often known as the “Warburg effect,” essential to fast proliferation and aggressive metastasis cells. Lactate, on other hand, a ubiquitous molecule in microenvironment (TME), generated primarily by cells undergoing glycolysis. To prevent intracellular acidification, malignant remove lactate along with H + , yet acidification TME inevitable. Not only does highly concentrated within serve substrate supply energy but it also works signal activate multiple pathways that enhance invasion, intratumoral angiogenesis, well immune escape. In this review, we aim discuss latest findings metabolism particularly capacity extracellular influence microenvironment. addition, examine current treatment techniques employing existing medications target interfere generation transport cancer therapy. New research shows targeting metabolism, lactate-regulated action are viable therapy strategies.

Language: Английский

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Targeting tumor exosomal circular RNA cSERPINE2 suppresses breast cancer progression by modulating MALT1-NF-𝜅B-IL-6 axis of tumor-associated macrophages

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: Feb. 17, 2023

Circular RNAs (circRNAs) have important regulatory functions in cancer, but the role of circRNAs tumor microenvironment (TME) remains unclear. Moreover, we also explore effects si-circRNAs loaded nanoparticles as therapeutic agent for anti-tumor vivo.We conducted bioinformatics analysis, qRT-PCR, EdU assays, Transwell co-culture system and multiple orthotopic xenograft models to investigate expression function circRNAs. Additionally, PLGA-based with were used evaluate potential nanotherapeutic strategy response.We identified oncogene SERPINE2 derived circRNA, named cSERPINE2, which was notably elevated breast cancer closely related poor clinical outcome. Functionally, exosomal cSERPINE2 shuttled associated macrophages (TAMs) enhanced secretion Interleukin-6 (IL-6), leading increased proliferation invasion cells. Furthermore, IL-6 turn EIF4A3 CCL2 levels within cells a positive feedback mechanism, further enhancing biogenesis promoting recruitment TAMs. More importantly, developed nanoparticle si-cSERPINE2, effectively attenuated progression vivo.Our study illustrates novel mechanism that mediates loop between TAMs promote progression, may serve promising treatment cancer.

Language: Английский

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Integrating single-cell analysis and machine learning to create glycosylation-based gene signature for prognostic prediction of uveal melanoma

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: March 23, 2023

Increasing evidence suggests a correlation between glycosylation and the onset of cancer. However, clinical relevance glycosylation-related genes (GRGs) in uveal melanoma (UM) is yet to be fully understood. This study aimed shed light on impact GRGs UM prognosis.To identify most influential UM, we employed AUCell WGCNA algorithms. The signature was established by integrating bulk RNA-seq scRNA-seq data. patients were separated into two groups based their risk scores, GCNS_low GCNS_high groups, differences clinicopathological correlation, functional enrichment, immune response, mutational burden, immunotherapy examined. role critical gene AUP1 validated through vitro vivo experiments.The comprised AUP1, HNMT, PARP8, ARC, ALG5, AKAP13, ISG20. GCNS significant prognostic factor for high correlated with poorer outcomes. Patients displayed heightened immune-related characteristics, such as cell infiltration scores. In experiments showed that knockdown led drastic reduction viability, proliferation, invasion capability cells.Our provides an independent predictor patient survival represents starting point further investigation UM. It offers novel perspective diagnosis treatment

Language: Английский

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Ononin inhibits triple-negative breast cancer lung metastasis by targeting the EGFR-mediated PI3K/Akt/mTOR pathway

Science China Life Sciences, Journal Year: 2024, Volume and Issue: 67(9), P. 1849 - 1866

Published: June 17, 2024

Language: Английский

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Multi‐omics analysis of disulfidptosis regulators and therapeutic potential reveals glycogen synthase 1 as a disulfidptosis triggering target for triple‐negative breast cancer

MedComm, Journal Year: 2024, Volume and Issue: 5(3)

Published: Feb. 28, 2024

Disruption of disulfide homeostasis during biological processes can have fatal consequences. Excess disulfides induce cell death in a novel manner, termed as "disulfidptosis." However, the specific mechanism disulfidptosis has not yet been elucidated. To determine cancer types sensitive to and outline corresponding treatment strategies, we firstly investigated crucial functions regulators pan-cancer at multi-omics levels. We found that different tumor expressed dysregulated levels regulators, most which had an impact on prognosis. Moreover, calculated activity score tumors validated it using multiple independent datasets. Additionally, was correlated with classic pathways various cancers. Disulfidptosis also associated immune characteristics could predict immunotherapy outcomes. Notably, regulator, glycogen synthase 1 (

Language: Английский

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ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 8, 2024

Abstract Background The hypoxic tumor microenvironment is a key factor that promotes metabolic reprogramming and vascular mimicry (VM) in ovarian cancer (OC) patients. ESM1, secreted protein, plays an important role promoting proliferation angiogenesis OC. However, the of ESM1 VM OC patients has not been determined. Methods Liquid chromatography coupled with tandem MS was used to analyze CAOV3 OV90 cells. Interactions between PKM2, UBA2, SUMO1 were detected by GST pull-down, Co-IP, molecular docking. effects ESM1-PKM2 axis on cell glucose metabolism analyzed based ECAR experiment. biological signaling cells tubule formation, transwell assay, RT‒PCR, Western blot, immunofluorescence, vivo xenograft experiments. Results Our findings demonstrated hypoxia induces upregulation expression through transcription HIF-1α. serves as crucial mediator interaction PKM2 facilitating SUMOylation subsequent formation dimers. This process Warburg effect facilitates nuclear translocation ultimately leading phosphorylation STAT3. These events contribute promotion glycolysis vasculogenic mimicry. Furthermore, our study revealed Shikonin effectively inhibits consequently preventing dimers thereby inhibiting glycolysis, fatty acid synthesis Conclusion increases transcriptional regulation HIF-1α induce dimerization via SUMOylation, which VM.

Language: Английский

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Predictive, preventive, and personalized medicine in breast cancer: targeting the PI3K pathway

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 3, 2024

Abstract Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase (PI3K) pathway has emerged as crucial contributor development, advancement, resistance This review article explores implications of PI3K in predictive, preventive, personalized medicine for BC. It emphasizes identification predictive biomarkers, such PIK3CA mutations, utility profiling guiding treatment decisions. The also discusses potential targeting preventive strategies customization therapy based on tumor stage, subtypes, genetic alterations. Overcoming inhibitors exploring combination therapies are addressed important considerations. While this field holds promise improving patient outcomes, further research clinical trials needed validate these approaches translate them into practice. Graphical

Language: Английский

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