Metabolic reprogramming in cholangiocarcinoma

Raggi, Chiara; Taddei, Maria Letizia; Rae, Colin; Braconi, Chiara; Marra, Fabio

doi:10.1016/j.jhep.2022.04.038

Cited by 89 publications

(76 citation statements)

References 156 publications

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“…This result is consistent with the mechanism by which cuproptosis depends on lipid metabolism. Lipid metabolism has been shown to be associated with malignant progression in a variety of tumors, including CCA ( 26 – 28 ). However, the link between lipid metabolism and cuproptosis needs to be further explored.…”

Section: Discussionmentioning

confidence: 99%

Establishment and experimental validation of a novel cuproptosis-related gene signature for prognostic implication in cholangiocarcinoma

Chen

Tong

et al. 2022

Front. Oncol.

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BackgroundCholangiocarcinoma (CCA) is a highly malignant, heterogeneous bile duct malignancy with poor treatment options. A novel type of cell death termed cuproptosis was recently demonstrated to closely correlate with tumor progression. To gain more insight into the role of cuproptosis in CCA, we investigated the prognostic implications of cuproptosis related genes (CRGs) and their relationship to the development of CCA.MethodsGene expression data for CCA were obtained from the European Bioinformatics Institute (EMBL-EBI) database. Least absolute shrinkage and selection operator (LASSO) penalized Cox regression was used to construct a prognostic risk model based on CRGs. RNA-seq, qRT−PCR and immunohistochemistry staining were used to verify the expression of CRGs in human CCA tissues or cell lines. Further in vitro experiments were performed to demonstrate the role of cuproptosis in CCA.ResultsWe established a 4-gene signature (ATP7A, FDX1, DBT and LIAS) that exhibited good stability and was an independent prognostic factor for CCA. Seventy-five CCA samples were divided into high- and low-risk groups based on the risk score. Enrichment analysis revealed increased extracellular activity in the high-risk group and increased lipid metabolic activity in the low-risk group. Moreover, the 4 signature genes were verified in clinical samples and cell lines by RNA-seq, qRT−PCR and immunohistochemistry. Further experiments confirmed that cuproptosis can significantly inhibit the viability of CCA cells. Knockdown of the key gene LIAS ameliorated the toxicity of cuproptosis to CCA cells.ConclusionWe established a 4-gene prognostic signature based on cuproptosis and explored the role of cuproptosis in CCA. The results provide an effective indicator for predicting the prognosis of cuproptosis in CCA.

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Section: Discussionmentioning

confidence: 99%

Establishment and experimental validation of a novel cuproptosis-related gene signature for prognostic implication in cholangiocarcinoma

Chen

Tong

et al. 2022

Front. Oncol.

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“…Immunotherapy, which allows for the elimination of primary and metastatic tumors by leveraging the host’s immune systems, has recently revolutionized cancer treatment. − Particularly, immune checkpoint blockade (ICB) therapies have gained remarkable success in treating several types of cancer by blocking the T-cell immunosuppressive pathway. , Despite significant efficacy, only a fraction of patients demonstrate a life-changing durable response to current mono-ICB therapies because of the inadequate tumor immunogenicity and immunosuppressive tumor microenvironment (ITME) . Previous studies have revealed that metabolic reprogramming in the tumor microenvironment (TME) can support the unrestricted proliferation and survival of cancer cells by generating immunosuppressive products. , This dysregulated metabolic activity dramatically restricts the function of immune cells, interferes with immune surveillance, and promotes immune evasion. , As a typical metabolic enzyme, indoleamine 2,3-dioxygenase (IDO) is overexpressed in many human tumors, which is often associated with poor prognosis . It exerts multiple immunosuppressive effects by catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn), including the suppression of effector T-cells, natural killer cells, and activation of regulatory T (Treg) cells. − Preclinical evidence confirms that the inhibition of the IDO enzyme can safely augment the antitumor efficiency of chemotherapy, radiotherapy, and ICB therapy. , Therefore, targeting metabolic pathways of tumors has emerged as a promising option for reversing immunosuppression.…”

Section: Introductionmentioning

confidence: 99%

“…8 Previous studies have revealed that metabolic reprogramming in the tumor microenvironment (TME) can support the unrestricted proliferation and survival of cancer cells by generating immunosuppressive products. 9,10 This dysregulated metabolic activity dramatically restricts the function of immune cells, interferes with immune surveillance, and promotes immune evasion. 11,12 As a typical metabolic enzyme, indoleamine 2,3dioxygenase (IDO) is overexpressed in many human tumors, which is often associated with poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

Photoactivatable Immunostimulatory Nanomedicine for Immunometabolic Cancer Therapy

Zhou

et al. 2022

J. Am. Chem. Soc.

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A rationally designed immunostimulant (CC@SiO2-PLG) with a photoactivatable immunotherapeutic function for synergetic tumor therapy is reported. This CC@SiO2-PLG nanoplatform comprises catalase and a photosensitizer (Ce6) co-encapsulated in a silica capsule, to which an immunostimulant is conjugated through a reactive oxygen species-cleavable linker. After accumulating in tumor tissue, CC@SiO2-PLG generates O2 to relieve tumor hypoxia and promotes the production of singlet oxygen (1O2) upon laser irradiation, resulting in not only tumor destruction but also the release of tumor-associated antigens (TAAs). Simultaneously, the linker breakage by the photoproduced 1O2 leads to the remote-controlled release of conjugated indoleamine 2,3-dioxygenase (IDO) inhibitor from CC@SiO2-PLG and consequent immunosuppressive tumor microenvironment reversion. The released TAAs in conjunction with the inhibition of the IDO-mediated tryptophan/kynurenine metabolic pathway induced a boosted antitumor immune response to the CC@SiO2-PLG-mediated phototherapy. Therefore, the growth of primary/distant tumors and lung metastases in a mouse xenograft model was greatly inhibited, which was not achievable by phototherapy alone.

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“…Lactate metabolism in tumor cells is significantly different from that in normal cells [ 9 ]. Unlike normal cells that gain energy by metabolizing glucose to pyruvate, which is then transported into the mitochondria for full oxidative phosphorylation, tumor cells rely mainly on aerobic glycolysis for energy and producing precursors for protein, lipid, and nucleotide synthesis [ 4 , 10 , 11 ]. In tumor cells, glucose is first catalyzed to pyruvate by enzymes such as hexokinase, 6-phosphofructokinase-1, and pyruvate kinase [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Tumor microenvironment-associated lactate metabolism regulates the prognosis and precise checkpoint immunotherapy outcomes of patients with lung adenocarcinoma

et al. 2022

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Background Despite the wide clinical application of checkpoint inhibitor immunotherapy in lung adenocarcinoma, its limited benefit to patients remains puzzling to researchers. One of the mechanisms of immunotherapy resistance may be the dysregulation of lactate metabolism in the immunosuppressive tumor microenvironment (TME), which can inhibit dendritic cell maturation and prevent T-cell invasion into tumors. However, the key genes related to lactate metabolism and their influence on the immunotherapeutic effects in lung adenocarcinoma have not yet been investigated in depth. Methods In this study, we first surveyed the dysregulated expression of genes related to lactate metabolism in lung adenocarcinoma and then characterized their biological functions. Using machine learning methods, we constructed a lactate-associated gene signature in The Cancer Genome Atlas cohort and validated its effectiveness in predicting the prognosis and immunotherapy outcomes of patients in the Gene Expression Omnibus cohorts. Results A 7-gene signature based on the metabolomics related to lactate metabolism was found to be associated with multiple important clinical features of cancer and was an independent prognostic factor. Conclusions These results suggest that rather than being simply a metabolic byproduct of glycolysis, lactate in the TME can affect immunotherapy outcomes. Therefore, the mechanism underlying this effect of lactate is worthy of further study.

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Metabolic reprogramming in cholangiocarcinoma

Cited by 89 publications

References 156 publications

Establishment and experimental validation of a novel cuproptosis-related gene signature for prognostic implication in cholangiocarcinoma

Establishment and experimental validation of a novel cuproptosis-related gene signature for prognostic implication in cholangiocarcinoma

Photoactivatable Immunostimulatory Nanomedicine for Immunometabolic Cancer Therapy

Tumor microenvironment-associated lactate metabolism regulates the prognosis and precise checkpoint immunotherapy outcomes of patients with lung adenocarcinoma

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