Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids

Gauna, Mikel Ruiz de; Biancaniello, Francesca; González-Romero, Francisco; Rodrigues, Pedro M.; Lapitz, Ainhoa; Gómez‐Santos, Beatriz; Olaizola, Paula; Matteo, Sabina Di; Aurrekoetxea, Igor; Labiano, Ibone; Nieva-Zuluaga, Ane; Benito‐Vicente, Asier; Apodaka-Biguri, Maider; Paiva, Nuno A.; Urturi, Diego Sáenz de; Buqué, Xabier; Delgado, Igotz; Martı́n, César; Azkargorta, Mikel; Elortza, Félix; Calvisi, Diego F.; Andersen, Jesper B.; Alvaro, Domenico; Cardinale, Vincenzo; Bujanda, Luís; Aspichueta, Patricia

doi:10.1002/hep.32344

Cited by 24 publications

(25 citation statements)

References 50 publications

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“…74 Additionally, in vitro and in a mouse model of AKT/NICD-driven cholangiocarcinogenesis, FASN and de novo lipogenesis were not required. 74,76 In contrast, CCA cells expressing low levels of FASN displayed high expression of FA uptake-related proteins and robust long-chain FA uptake, as a compensatory mechanism. Specifically, Li, Che, et al, 74 identified a role for FATP1 (SLC27A1), a member of the FA transport protein family.…”

Section: Cca and Lipid Metabolismmentioning

confidence: 99%

Metabolic reprogramming in cholangiocarcinoma

Raggi

Taddei

Rae

et al. 2022

Journal of Hepatology

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Section: Cca and Lipid Metabolismmentioning

confidence: 99%

Metabolic reprogramming in cholangiocarcinoma

Raggi

Taddei

Rae

et al. 2022

Journal of Hepatology

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“…Notably, we observed a trend towards a reduction in HexCer and LacCer expression in G3 compared with G2 iCCA-derived EVs. Like other tumors, CCA is highly dependent on lipid and glucose metabolism [22,37]. Thus, similarly to the highly proliferative CCA cell lines, that are dependent upon increased lipid uptake and metabolization via fatty acid oxidation [22], poorly-differentiated tumors may require more glucose than the moderatelydifferentiated ones to sustain their metabolic demand.…”

Section: Discussionmentioning

confidence: 99%

“…Like other tumors, CCA is highly dependent on lipid and glucose metabolism [22,37]. Thus, similarly to the highly proliferative CCA cell lines, that are dependent upon increased lipid uptake and metabolization via fatty acid oxidation [22], poorly-differentiated tumors may require more glucose than the moderatelydifferentiated ones to sustain their metabolic demand. Therefore, the degradation of glycated ceramides could represent an additional source of glucose which could account for the accumulation of Cer, eventually removed by EVs.…”

Section: Discussionmentioning

confidence: 99%

“…NHC cells were isolated from normal liver tissue specimens and maintained as previously described [22].…”

Section: Cell Culturesmentioning

confidence: 99%

“…In particular, ceramide (Cer) and its metabolite ceramide 1-phosphate play key roles in a number of in ammation-associated diseases such as cystic brosis [17,18], lung cancer [19] and nonalcoholic fatty liver disease [20,21]. SPL metabolism is widely dysregulated in chronic liver disease and liver cancer [16,22], while Cer and sphingomyelin (SM) content undergoes important remodeling in various CCA cell lines [22].…”

Section: Introductionmentioning

confidence: 99%

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Ceramide present in cholangiocarcinoma-derived extracellular vesicle induces a pro-inflammatory state in monocytes.

Oliviero

Dei

Zulueta

et al. 2023

Preprint

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Cholangiocarcinoma (CCA) is a rare cancer with global increasing incidence. Extracellular vesicles (EV) contribute to many of the hallmarks of cancer through transfer of their cargo molecules. The sphingolipid (SPL) profile of intrahepatic CCA (iCCA)-derived EVs was characterized by liquid chromatography-tandem mass spectrometry analysis. The effect of iCCA-derived EVs as mediators of inflammation was assessed on monocytes by flow cytometry. iCCA-derived EVs showed downregulation of all SPL species. Of note, poorly-differentiated iCCA-derived EVs showed a higher ceramide and dihydroceramide content compared with moderately-differentiated iCCA-derived EVs. Higher ceramide and dihydroceramide content was associated with vascular invasion, larger tumor size and relevant expression of pro-inflammatory cytokines in monocytes. Inhibition of synthesis of ceramide with Myriocin, a specific inhibitor of the serine palmitoyl transferase, reduced the pro-inflammatory capacity of iCCA-derived EVs, demonstrating the role for ceramide as mediator of inflammation in iCCA. In conclusion, iCCA-derived EVs may facilitate iCCA progression by exporting the excess of pro-apoptotic and pro-inflammatory ceramides.

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Construction of an immune‐related prognostic model and potential drugs screening for esophageal cancer based on bioinformatics analyses and network pharmacology

Qi,

et al. 2024

Immunity Inflam & Disease

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BackgroundEsophageal cancer (ESCA) is a highly invasive malignant tumor with poor prognosis. This study aimed to discover a generalized and high‐sensitivity immune prognostic signature that could stratify ESCA patients and predict their overall survival, and to discover potential therapeutic drugs by the connectivity map.MethodsThe key gene modules significantly related to clinical traits (survival time and state) of ESCA patients were selected by weighted gene coexpression network analysis (WCGNA), then the univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to construct a 15‐immune‐related gene prognostic signature.ResultsThe immune‐related risk model was related to clinical and pathologic factors and remained an effective independent prognostic factor. Enrichment analyses revealed that the differentially expressed genes (DEGs) of the high‐ and low‐risk groups were associated with tumor cell proliferation and immune mechanisms. Based on the gathered data, a small molecule drug named perphenazine (PPZ) was elected. The pharmacological analysis indicates that PPZ could help in adjuvant therapy of ESCA through regulation of metabolic process and cellular proliferation, enhancement of immunologic functions, and inhibition of inflammatory reactions. Furthermore, molecular docking was performed to explore and verify the PPZ‐core target interactions.ConclusionWe succeed in structuring the immune‐related prognostic model, which could be used to distinguish and predict patients' survival outcome, and screening a small molecule drug named PPZ. Prospective studies also are needed to further validate its analytical accuracy for estimating prognoses and confirm the potential use of PPZ for treating ESCA.

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Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids

Abstract: Background and Aims: Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with a dismal prognosis. We investigated if lipid metabolism is disrupted in CCA and its role in tumor proliferation.

Cited by 24 publications

References 50 publications

Metabolic reprogramming in cholangiocarcinoma

Metabolic reprogramming in cholangiocarcinoma

Ceramide present in cholangiocarcinoma-derived extracellular vesicle induces a pro-inflammatory state in monocytes.

Construction of an immune‐related prognostic model and potential drugs screening for esophageal cancer based on bioinformatics analyses and network pharmacology

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