Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma

Dong, Liangqing; Lu, Da Yong; Chen, Ran; Lin, Youpei; Zhu, Hongwen; Zhang, Zhou; Cai, Shangli; Cui, Peng; Song, Guohe; Rao, Dongning; Yi, Xinpei; Wu, Yingcheng; Song, Nixue; Liu, Fen; Zou, Yunhao; Zhang, Shu; Zhang, Xiaoming; Wang, Xiaoying; Qiu, Shuang–Jian; Zhou, Ji; Wang, Shisheng; Zhang, Xu; Shi, Yongyong; Figeys, Daniel; Li, Ding; Wang, Pei; Zhang, Bing; Rodriguez, Henry; Gao, Qiang; Gao, Daming; Zhou, Hu; Fan, Jia

doi:10.1016/j.ccell.2021.12.006

Cited by 194 publications

(193 citation statements)

References 113 publications

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“…(2) The second cohort enrolled 255 patients from the FU-iCCA cohort. The bulk RNA-seq data of 255 patients with ICC from Zhongshan Hospital, Fudan University (FU-iCCA cohort) ( 19 ), were analyzed and are available in the biosino NODE database (NODE database: OEP001105). (3) The third cohort recruited a cohort of 264 consecutive patients undergoing curative resection for ICC from 2012 to 2017 in Zhongshan Hospital (ZSH cohort).…”

Section: Methodsmentioning

confidence: 99%

Dissecting Intra-Tumoral Changes Following Immune Checkpoint Blockades in Intrahepatic Cholangiocarcinoma via Single-Cell Analysis

et al. 2022

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PurposeTo dissect the tumor ecosystem following immune checkpoint blockades (ICBs) in intrahepatic cholangiocarcinoma (ICC) at a single-cell level.MethodsSingle-cell RNA sequencing (scRNA-seq) data of 10 ICC patients for the ICB clinical trial were extracted from GSE125449 and systematically reanalyzed. Bulk RNA-seq data of 255 ICC patients were analyzed. Infiltration levels of SPP1+CD68+ tumor-associated macrophages (TAMs) were examined by dual immunofluorescence (IF) staining in 264 resected ICC samples. The correlation between SPP1+ TAMs and clinicopathological features as well as their prognostic significance was evaluated.ResultsAmong the 10 patients, five received biopsy at baseline, and others were biopsied at different timings following ICBs. Single-cell transcriptomes for 5,931 cells were obtained. A tighter cellular communication network was observed in ICB-treated ICC. We found a newly emerging VEGF signaling mediated by PGF-VEGFR1 between cancer-associated fibroblasts (CAFs) and endothelial cells in ICC following ICBs. SPP1 expression was dramatically upregulated, and SPP1+ TAM gene signatures were enriched in TAMs receiving ICB therapy. We also identified SPP1+ TAMs as an independent adverse prognostic indicator for survival in ICC.ConclusionOur analyses provide an overview of the altered tumor ecosystem in ICC treated with ICBs and highlight the potential role of targeting CAFs and SPP1+TAMs in developing a more rational checkpoint blockade-based therapy for ICC.

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Section: Methodsmentioning

confidence: 99%

Dissecting Intra-Tumoral Changes Following Immune Checkpoint Blockades in Intrahepatic Cholangiocarcinoma via Single-Cell Analysis

et al. 2022

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“…Complement activation and acute phase response signaling were among the top categories in the IPA analysis. Recent studies have described the presence and pro-tumorigenic role of bacteria and bacterial products in human CCA tissues [ 4 , 40 ]. This driving factor was also present in our model, as we were able to detect significantly increased bacterial DNA levels in liver tissues from TAA-treated rats (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…CCAs are molecularly heterogeneous tumors, and this characteristic extends beyond their anatomical classification. Recent transcriptomic, genomic, proteogenomic and epigenomic analyses have identified different molecular subclasses indicative of potential carcinogenic mechanisms leading to CCA development [ 3 , 4 ]. The complex molecular profile of CCAs may underlie their high resistance to chemotherapy, targeted agents and immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming

Colyn

Álvarez‐Sola

Latasa

et al. 2022

J Exp Clin Cancer Res

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Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + CCl4 + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-KRASG12D cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant KRASG12D can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, KRASG12D promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. KRASG12D CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA.

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“…Among these mutations, point mutations in KRAS codon 12 are probably the most common event, which accounts for approximately 80% of KRAS mutation [ 21 ]. A recent study also showed that, compared with a western iCCA cohort (the Memorial Sloan Kettering Cancer Center cohort), the China Fudan-iCCA cohort showed higher KRAS mutation frequency and lower IDH1, ARID1A, and TERT mutation frequencies [ 23 ]. Most studies have concluded that there is a negative influence on prognosis of patients with a KRAS mutation whether or not they have undergone surgery for other solid tumors [ 24 , 25 ] and a correlation between oncogenic KRAS mutations and PD-L1 expression in cancers has also been emphasized [ 10 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

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

Gao

Chen

et al. 2022

Cancer Cell Int

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

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Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma

Cited by 194 publications

References 113 publications

Dissecting Intra-Tumoral Changes Following Immune Checkpoint Blockades in Intrahepatic Cholangiocarcinoma via Single-Cell Analysis

Dissecting Intra-Tumoral Changes Following Immune Checkpoint Blockades in Intrahepatic Cholangiocarcinoma via Single-Cell Analysis

New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming

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

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