Tumor-derived exosomal LINC01812 induces M2 macrophage polarization to promote perineural invasion in cholangiocarcinoma DOI Creative Commons

Qinlei Wang,

Zhaowei Sun,

Jingyun Guo

et al.

Cancer Letters, Journal Year: 2025, Volume and Issue: 617, P. 217596 - 217596

Published: March 12, 2025

M2 macrophages play a critical role in the tumor microenvironment of invasive solid tumors. They are closely associated with perineural invasion (PNI) and often linked to poor prognosis. In this context, tumor-derived exosomes serve as important mediators intercellular communication. However, relationship between cell-induced PNI cholangiocarcinoma remains unexplored. study, we utilized multiplex immunofluorescence transcriptomic sequencing demonstrate upregulation LINC01812 tissues its positive correlation macrophage infiltration. Exosomal lncRNA sequencing, exosome uptake experiments, RNA pull-down assays, mass spectrometry analysis demonstrated that can internalize exosomal promote phenotype cells. Additionally, Transwell vitro cocultures dorsal root ganglia confirmed significantly enhances nerve infiltration cells via macrophages. The findings study indicate containing derived from induce polarization facilitate infiltration, thereby providing new potential therapeutic targets for managing cholangiocarcinoma.

Language: Английский

FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions DOI

Masuko Katoh,

Yohann Loriot,

Giovanni Brandi

et al.

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(4), P. 312 - 329

Published: Feb. 29, 2024

Language: Английский

Citations

60
The causal relationship between gut microbiota and biliary tract cancer: comprehensive bidirectional Mendelian randomization analysis DOI Creative Commons
Kui Wang,

Suijian Wang,

Xianzheng Qin

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2024, Volume and Issue: 14

Published: March 15, 2024

Background Growing evidence has shown that gut microbiome composition is associated with Biliary tract cancer (BTC), but the causality remains unknown. This study aimed to explore causal relationship between microbiota and BTC, conduct an appraisal of microbiome’s utility in facilitating early diagnosis BTC. Methods We acquired summary data for Genome-wide Association Studies (GWAS) pertaining BTC (418 cases 159,201 controls) from Biobank Japan (BBJ) database. Additionally, GWAS relevant (N = 18,340) were sourced MiBioGen consortium. The primary methodology employed analysis consisted Inverse Variance Weighting (IVW). Evaluations sensitivity carried out through utilization multiple statistical techniques, encompassing Cochrane’s Q test, MR-Egger intercept evaluation, global test MR-PRESSO, a leave-one-out methodological analysis. Ultimately, reverse Mendelian Randomization was conducted assess potential reciprocal causality. Results outcomes derived IVW substantiated presence Family Streptococcaceae (OR 0.44, P 0.034), Veillonellaceae 0.46, 0.018), Genus Dorea 0.29, 0.041) exerted protective influence against Conversely, Class Lentisphaeria 2.21, 0.017), Lachnospiraceae FCS020 Group 2.30, 0.013), Order Victivallales 0.017) adverse impact. To any effect, we used as exposure outcome, this revealed associations five different types microbiota. disclosed absence empirical indicators either heterogeneity or pleiotropy. Conclusion investigation represents inaugural identification indicative supporting beneficial detrimental relationships risk determined MR methodologies. These could hold significance formulation individualized therapeutic strategies at prevention survival enhancement.

Language: Английский

Citations

9
Causal relationship between immune cell phenotypes and risk of biliary tract cancer: evidence from Mendelian randomization analysis DOI Creative Commons

YaLan Hu,

Kui Wang, Yuhua Chen

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 10, 2024

Biliary tract cancer stands as a prevalent illness, posing significant risks to human health, where immune cells are pivotal in both its development and recovery processes. Due the diverse functionalities exhibited by different cell phenotypes within organism, relatively limited research on their relationship with biliary cancer, this study employed Mendelian randomization (MR) explore potential association, thereby aiding better understanding of causal link between cancer.

Language: Английский

Citations

9
Noncanonical TRAIL Signaling Promotes Myeloid-Derived Suppressor Cell Abundance and Tumor Growth in Cholangiocarcinoma DOI Creative Commons
Emilien Loeuillard, Binbin Li, Hannah E. Stumpf

et al.

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2024, Volume and Issue: 17(5), P. 853 - 876

Published: Jan. 1, 2024

Proapoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling as a cause of cancer cell death is well-established mechanism. However, TRAIL-receptor (TRAIL-R) agonists have had very limited anticancer activity in human beings, challenging the concept TRAIL potent agent. Herein, we aimed to define mechanisms by which TRAIL+ cells can leverage noncanonical myeloid-derived suppressor (MDSCs) promoting their abundance murine cholangiocarcinoma (CCA). Multiple immunocompetent syngeneic, orthotopic models CCA were used. Single-cell RNA sequencing and cellular indexing transcriptomes epitopes CD45+ tumors from different was conducted. In multiple CCA, implantation into Trail-r-/- mice resulted significant reduction volumes compared with wild-type mice. Tumor-bearing decrease MDSCs owing attenuation MDSC proliferation. Noncanonical consequent nuclear factor-κB activation facilitated enhanced immune showed enrichment signature MDSCs. Moreover, resistant TRAIL-mediated apoptosis expression FLICE inhibitory protein, an inhibitor proapoptotic signaling. Accordingly, protein knockdown sensitized apoptosis. Finally, cell-restricted deletion Trail significantly reduced burden. Our findings highlight therapeutic potential targeting for treatment poorly immunogenic cancer.

Language: Английский

Citations

8
Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via exosomes in gastrointestinal tumors DOI Creative Commons

Longyang Cao,

Hong Ouyang

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Feb. 23, 2024

Gastrointestinal (GI) tumors are a significant global health threat, with high rates of morbidity and mortality. Exosomes contain various biologically active molecules like nucleic acids, proteins, lipids can serve as messengers for intercellular communication. They play critical roles in the exchange information between tumor cells microenvironment (TME). The TME consists mesenchymal components extracellular matrix (ECM), fibroblasts being most abundant cell type mesenchyme. Cancer-associated (CAFs) derived from normal stem that activated TME. CAFs secrete exosomes to modulate proliferation, invasion, migration, drug resistance, other biological processes tumors. Additionally, manipulate function behavior through direct cell-cell interactions. This review provides summary crosstalk GI exosomes, along potential underlying mechanisms.

Language: Английский

Citations

8
N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1 DOI Creative Commons
Jing Li, Xiaohong Xu, Kaihao Xu

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: April 20, 2024

Refractoriness to surgical resection and chemotherapy makes intrahepatic cholangiocarcinoma (ICC) a fatal cancer of the digestive system with high mortality poor prognosis. Important function invests circRNAs tremendous potential in biomarkers therapeutic targets. Nevertheless, it is still unknown how contribute evolution ICC. CircRNAs paired ICC adjacent tissues were screened by sequencing. To explore impact on development, experiments involving gain loss conducted. Various experimental techniques, including quantitative real-time PCR (qPCR), western blotting, RNA immunoprecipitation (RIP), luciferase reporter assays, pull-down, chromatin (ChIP), ubiquitination assays so employed identify molecular regulatory role circRNAs. Herein, we reported new circRNA, which originates from exon 9 15 SLCO1B3 gene (named circSLCO1B3), orchestrated progression promoting tumor proliferation, metastasis immune evasion. We found that circSLCO1B3 was highly overexpressed related lymphatic metastasis, sizes, differentiation. Mechanically, not only promoted proliferation via miR-502-5p/HOXC8/SMAD3 axis, but also eradicated anti-tumor immunity suppressing ubiquitin-proteasome-dependent degradation PD-L1 E3 ubiquitin ligase SPOP. further methyltransferase like 3 (METTL3) mediated m6A methylation stabilizes its expression. Our findings indicate prognostic marker target patients. Taken together, m6A-modified correlated prognosis enhancing potentiating HOXC8 expression, inducing evasion antagonizing degradation. These results suggest for

Language: Английский

Citations

8
Manganese-based immunotherapy synergized with novel supramolecular hydrogel: Advancing localized immune activation strategies in squamous cell carcinoma DOI Creative Commons
Tianqing Wang, Xiaopei Hu, Xin Tian

et al.

Materials & Design, Journal Year: 2025, Volume and Issue: unknown, P. 113632 - 113632

Published: Jan. 1, 2025

Language: Английский

Citations

1
Overcoming immunotherapy resistance in gastric cancer: insights into mechanisms and emerging strategies DOI Creative Commons

D.Y. Luo,

Jing Zhou, Shuiliang Ruan

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 7, 2025

Abstract Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options in advanced stages. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1, has emerged as promising therapeutic approach. However, significant proportion patients exhibit primary or acquired resistance, limiting the overall efficacy immunotherapy. This review provides comprehensive analysis mechanisms underlying immunotherapy resistance GC, including role tumor microenvironment, dynamic PD-L1 expression, compensatory activation other checkpoints, and genomic instability. Furthermore, explores GC-specific factors such molecular subtypes, unique evasion mechanisms, impact Helicobacter pylori infection. We also discuss emerging strategies to overcome combination therapies, novel immunotherapeutic approaches, personalized based on genomics microenvironment. By highlighting these key areas, this aims inform future research directions clinical practice, ultimately improving outcomes for GC undergoing

Language: Английский

Citations

1
Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma DOI Creative Commons
Margaret Wheless, Rajiv Agarwal, Laura W. Goff

et al.

Current Treatment Options in Oncology, Journal Year: 2024, Volume and Issue: 25(1), P. 127 - 160

Published: Jan. 1, 2024

Biliary tract cancers are molecularly and anatomically diverse which include intrahepatic cholangiocarcinoma, extrahepatic (perihilar distal) gallbladder cancer. While recognized as distinct entities, the rarer incidence of these combined with diagnostic challenges in classifying anatomic origin has resulted clinical trials guideline recommended strategies being generalized patients all types biliary In this review, we delve into unique aspects, subtype-specific trial outcomes, multidisciplinary management cholangiocarcinoma. When resectable, definitive surgery followed by adjuvant chemotherapy (sometimes selective radiation/chemoradiation) is current standard care. Due to high recurrence rates, there growing interest use upfront/neoadjuvant therapy improve surgical outcomes downstage who may not initially be resectable. Select perihilar cholangiocarcinoma successfully treated novel approaches such liver transplant. advanced disease setting, combination gemcitabine cisplatin remains base for systemic was recently improved upon addition immune checkpoint blockade doublet reported TOPAZ-1 KEYNOTE-966 trials. Second-line all-comer treatments remain limited both options efficacy, so participation should strongly considered. With increased molecular testing, detection actionable mutations opportunities receive indicated targeted therapies on rise most significant driver survival stage disease. Though currently reserved second or later line, future looking at moving earlier treatment settings immunotherapy. cross-disciplinary surgical, medical, radiation oncology, patient-centered care also collaboration endoscopists, palliative specialists, nutritionists global patient outcomes.

Language: Английский

Citations

7
Syngeneic murine models with distinct immune microenvironments represent subsets of human intrahepatic cholangiocarcinoma DOI Creative Commons
Jennifer L. Tomlinson, Binbin Li, Jingchun Yang

et al.

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 80(6), P. 892 - 903

Published: March 7, 2024

•Transposase-mediated transduction of Fbxw7ΔF and Akt into the biliary epithelium promotes CCA carcinogenesis.•Murine cells derived from Fbxw7ΔF/Akt tumors can be implanted orthotopically mouse livers to generate a syngeneic model (FAC).•This recapitulates critical phenotypic pathological elements human iCCA.•Syngeneic murine models with different genetic drivers correspond subsets CCA.•Syngeneic iCCA display genotype-immune microenvironment phenotype correlation differential responses immunotherapy. Background & AimsCholangiocarcinoma (CCA) is poorly immunogenic malignancy associated limited survival. Syngeneic immunocompetent are an essential tool elucidate tumor immune (TIME), understand mechanisms evasion, test novel immunotherapeutic strategies. The scope this study was develop characterize distinct drivers, correlate genomics, immunobiology, therapeutic response.MethodsA multifaceted approach including scRNA-seq, CITE-seq, whole exome bulk RNA sequencing employed. FDA-approved PD-1/PD-L1 antibodies were tested in humanized mice (HuPD-H1).ResultsA intrahepatic (iCCA) driven by intrabiliary that mimics generated. From tumors, cell line (FAC) characteristics developed. Established SB1 (YAPS127A/Akt) KPPC (KrasG12Dp53L/L) compared FAC model. Although had transcriptomic similarities, they substantial differences as well. Mutation patterns FAC, SB1, matched mutational signatures Western Japanese patient cohorts. high mutation burden. T cell-infiltrated TIME, while preponderance suppressive myeloid cells. Moreover, tumor-bearing HuPD-H1 displayed nivolumab or durvalumab.ConclusionsSyngeneic between genotype TIME phenotype, immunotherapies. This underscores importance leveraging multiple preclinical immunotherapy CCA.Impact implicationsUnderstanding relationship unmet need cholangiocarcinoma (CCA). Herein, we use demonstrate models, which information will help guide other studies. Additionally, it emphasizes checkpoint inhibition patients not "one-size-fits-all" approach. Our observations suggest that, for targeted therapies, should stratified selected treatment according their genetics. Cholangiocarcinoma response. A (HuPD-H1). durvalumab. CCA.

Language: Английский

Citations

6