KRAS acting through ERK signaling stabilizes PD-L1 via inhibiting autophagy pathway in intrahepatic cholangiocarcinoma

Cancer Cell International, Год журнала: 2022, Номер 22(1)

Опубликована: Март 19, 2022

While the correlation between PD-L1 expression and KRAS mutation has been previously reported in other solid tumors such as non-small cell lung cancer (NSCLC), whether can be modulated by ERK signaling downstream of intrahepatic cholangiocarcinoma (iCCA) underlying molecular regulatory mechanism remain unclear.The ERK, p-ERK, autophagy markers following knockdown or Ras/Raf/MEK/ERK inhibitors treatment was examined two human iCCA lines (HuCCT1 RBE) using western blotting immunofluorescence. Both pharmacological short-interfering RNA against ATG7 were applied to inhibit autophagy. The apoptosis rates detected flow cytometry CCK-8 after co-culturing with CD3/CD28-activated CD8+ T lymphocytes. Immunohistochemistry detect p-ERK 92 tissues.The present study demonstrated that level distinctly reduced KRAS-mutated when inhibited phosphorylation levels lowered. positive association also verified tissue samples. Moreover, inhibition induced activation. inhibiting via genetically silencing partially reversed caused inhibition. In addition, ERK-mediated down-regulation pathways cells co-cultured lymphocytes vitro.Our results suggest contributes reduction through pathway iCCA. As a supplement anti-PD-1/PD-L1 immunotherapy, ERK-targeted therapy may serve potentially novel strategy for

Язык: Английский

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Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies

Gut, Год журнала: 2023, Номер 73(6), С. 966 - 984

Опубликована: Ноя. 24, 2023

Objectives Cholangiocarcinoma (CCA) is a heterogeneous malignancy with high mortality and dismal prognosis, an urgent clinical need for new therapies. Knowledge of the CCA epigenome largely limited to aberrant DNA methylation. Dysregulation enhancer activities has been identified affect carcinogenesis leveraged therapies but uninvestigated in CCA. Our aim identify potential therapeutic targets different subtypes through profiling. Design Integrative multiomics activity profiling diverse was performed. A panel cell lines, patient-derived line-derived xenografts were used study enriched pathways vulnerabilities. NanoString, multiplex immunohistochemistry staining single-cell spatial transcriptomics explore immunogenicity Results We three distinct groups, associated etiologies unique pathways. Drug inhibitors reduced tumour growth vitro vivo models. The first group (ESTRO), mostly fluke-positive CCAs, displayed activation estrogen signalling sensitive MTOR inhibitors. Another (OXPHO), BAP1 IDH -mutant activated oxidative phosphorylation pathways, Immune-related final (IMMUN), made up immunogenic subtype aristolochic acid (AA) mutational signatures. Intratumour differences AA mutation load correlated intratumour variation immune populations. Conclusion elucidates mechanisms underlying dysregulation deepens understanding tumourigenesis processes subtypes, significant therapeutics benefits.

Язык: Английский

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Multi-omics-driven discovery of invasive patterns and treatment strategies in CA19-9 positive intrahepatic cholangiocarcinoma

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Ноя. 15, 2024

Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor with poor prognosis, predominantly CA19-9 positive. High levels correlate increased aggressiveness and worse outcomes. This study employs multi-omics analysis to reveal molecular features identify therapeutic targets of positive ICC, aiming support individualized treatment. Data from seven clinical cohorts, two whole-exome sequencing six RNA sequencing/microarray one proteomic cohort, 20 single-cell samples, spatial transcriptome sample were analyzed. Key findings validated on tissue microarrays 52 ICC samples. exhibited poorer OS (median 24.1 v.s. 51.5 months) RFS 11.7 28.2 compared negative group (all P < 0.05). Genomic revealed higher KRAS mutation frequency in the greater prevalence IDH1/2 mutations Transcriptomic indicated upregulated glycolysis pathways ICC. Single-cell identified specific glycolysis-related cell subclusters associated including Epi_SLC2A1, CAF_VEGFA, Mph_SPP1. Higher hypoxia led metabolic reprogramming promoted these cells' formation. These cells formed interactive communities promoting epithelial-mesenchymal transition (EMT) angiogenesis. Drug sensitivity potential drugs. systematically elucidated clinical, genomic, transcriptomic, immune It reveals glycolysis-associated cellular their cancer-promoting mechanisms, enhancing our understanding laying groundwork for strategies.

Язык: Английский

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Neoadjuvant Multiagent Systemic Therapy Approach to Liver Transplantation for Perihilar Cholangiocarcinoma

Transplantation Direct, Год журнала: 2025, Номер 11(3), С. e1760 - e1760

Опубликована: Фев. 7, 2025

Background. Perihilar cholangiocarcinoma (phCCA) has excellent outcomes following liver transplantation (LT). Neoadjuvant radiation-based locoregional therapy is standard-of-care. Gemcitabine and cisplatin (gem/cis) combination systemic therapies have improved in advanced settings, but their efficacy pre-LT not been studied. Methods. We review our experience neoadjuvant gem/cis alone versus approaches. Patients with phCCA undergoing LT at a single center between January 2008 February 2023 were identified retrospectively. was categorized as (ST) alone, or any ST radiotherapy (RT). Outcomes posttransplant overall survival (OS), recurrence-free (RFS), waitlist time, pathologic tumor response. Results. During study period, 27 patients underwent LT. One patient decompensated excluded. Median age 61 y (interquartile range, 53–68 y) 14 (54%) male. Of 26 patients, 12 (46%) received RT. Six RT ST. time 199 d 98–405 d) did differ by regimen. Explanted tumors predominantly T1 stage, without lymphovascular invasion nodal involvement. Neither features nor percent necrosis differed OS probabilities 1 3 84% 55% for the cohort. There no significant difference RFS when stratified Conclusions. Post-LT OS, RFS, response similar 2 groups. who do undergo may still be considered under appropriate institution-based protocols that adhere to other established criteria.

Язык: Английский

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Effect of comprehensive cancer genomic profiling on therapeutic strategies and clinical outcomes in patients with advanced biliary tract cancer: A prospective multicenter study

Frontiers in Oncology, Год журнала: 2022, Номер 12

Опубликована: Сен. 2, 2022

Characterization of the genomic landscape biliary tract cancer (BTC) may lead to applying genotype-matched therapy for patients with this disease. Evidence that comprehensive profiling (CGP) guides improve clinical outcomes is building. However, significance CGP in BTC remains unclarified practice. Therefore, purposes study were assess utility and identify associations between alterations BTC. In prospective analysis, detection rates actionable access analyzed 72 advanced who had undergone commercial CGP. Cox regression analyses assessed relationships overall survival detected The most common TP53 (41, 56.9%), followed by CDKN2A/B (24, 33.3%/20, 27.8%), KRAS (20, 27.8%). Actionable identified 58.3% (42/72) patients. Detection FGFR2 fusions, IDH1 mutations, BRAF V600E low cohort. Eight (11.1%) received therapy. For intrahepatic cholangiocarcinoma (ICC), loss was associated shorter survival. These real-world data demonstrate can therapeutic options as a poor prognostic factor ICC. Thus, provides rationale considering planning strategies

Язык: Английский

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