Targeted Metabolomics Identifies Plasma Biomarkers in Mice with Metabolically Heterogeneous Melanoma Xenografts

Weber, Daniela D.; Thapa, Maheshwor; Aminzadeh-Gohari, Sepideh; Redtenbacher, Anna-Sophia; Catalano, Luca; Feichtinger, René G.; Koelblinger, Peter; Dallmann, Guido; Emberger, Michael; Kofler, Barbara; Lang, Roland

doi:10.3390/cancers13030434

Cited by 12 publications

(12 citation statements)

References 79 publications

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“…Targeted metabolomics based on the UPLC-MS/MS technique has been applied in many studies. 13 − 16 As we know, when operating in target metabolomics, the mass spectrometer is more sensitive and obtains ion data of specific predetermined mass-to-charge ratios (M/Z) and their specific fragments. Although the targeted method generates a narrower metabolome view, researchers are more confident in the output results, because UPLC-MS/MS could identity the signals and the method can be fully validated; thus, absolute quantification is possible.…”

Section: Discussionmentioning

confidence: 99%

Serum Amino Acid Profiles Predict the Development of Hepatocellular Carcinoma in Patients with Chronic HBV Infection

Zheng

Yang

et al. 2022

ACS Omega

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Background: The study aimed to find out the alterations in serum amino acid (AA) profiles and to detect their relationship with carcinoma formation. Methods: Targeted metabolomics based on ultraperformance liquid chromatography triple quadrupole mass spectrometry to quantitatively analyze serum AA levels in 136 hepatitis B (CHB) patients and 93 hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. Results: It was shown that decreased serum levels of leucine, lysine, threonine, tryptophan, valine, serotonin, and taurine were observed in more HCC patients than CHB patients, but the serum phenylalanine level was increased. Serum valine and serotonin were lower in Class C than Class A and Class B in HCC patients. Accompanied with the higher score of Model for End-Stage Liver Disease, serum phenylalanine was increased not only in CHB patients but also in HCC patients. The serum level of phenylalanine increased in the decompensated stage more than in the compensated stage, while serum leucine and serotonin significantly decreased. Serum serotonin still had significant differences between CHB and HCC both in the HBV desoxyribonucleic acid (HBV-DNA) negative group and in the HBV-DNA positive group. Furthermore, it was shown that the tryptophan ratio, branched-chain amino acids (BCAA)/aromatic amino acids ratio, BCAAs/tyrosine ratio, Fischer’s ratio, and serotonin-to-tryptophan ratio significantly decreased, while the tyrosine ratio and the kynurenine-to-tryptophan ratio increased in HCC patients more than those in CHB. Conclusions: A distinct metabolite signature of some specific serum amino acids was found between CHB and HCC patients, which may help predict the development of HCC at an early stage.

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Section: Discussionmentioning

confidence: 99%

Serum Amino Acid Profiles Predict the Development of Hepatocellular Carcinoma in Patients with Chronic HBV Infection

Zheng

Yang

et al. 2022

ACS Omega

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“…Although we were expecting plasma metabolites being differentially expressed among the plasma of non-tumor-bearing versus tumor-bearing mice, we could not find any statistically significant difference between these two datasets. In a recent report, Weber et al (2021) by using targeted metabolomics have been able to identify seven metabolites differentially expressed in plasma samples of heterogeneous melanoma xenografts, including tiglylcarnitine, beta-alanine, PC ae C42:4, sarcosine, Hex2Cer (d18:1/16:0), Hex2Cer (d18:1/20:0), and p-Cresol sulfate. It is conceivable to speculate that, as a consequence of the different biological settings, our metabolomic profiling did not reveal most of these metabolites, nor, if identified, was it able to determine significant differences in their levels.…”

Section: Discussionmentioning

confidence: 99%

Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor Growth

Vecchio

Caiazza

Mimmi

et al. 2021

Front. Cell Dev. Biol.

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Tumor interstitial fluid (TIF) surrounds and perfuses tumors and collects ions, metabolites, proteins, and extracellular vesicles secreted by tumor and stromal cells. Specific metabolites, accumulated within the TIF, could induce metabolic alterations of immune cells and shape the tumor microenvironment. We deployed a metabolomic approach to analyze the composition of melanoma TIF and compared it to the plasma of C57BL6 mice, engrafted or not with B16-melanoma cells. Among the classes of metabolites analyzed, monophosphate and diphosphate nucleotides resulted enriched in TIF compared to plasma samples. The analysis of the effects exerted by guanosine diphosphate (GDP) and uridine diphosphate (UDP) on immune response revealed that GDP and UDP increased the percentage of CD4+CD25+FoxP3– and, on isolated CD4+ T-cells, induced the phosphorylation of ERK, STAT1, and STAT3; increased the activity of NF-κB subunits p65, p50, RelB, and p52; increased the expression of Th1/Th17 markers including IFNγ, IL17, T-bet, and RORγt; and reduced the expression of IL13, a Th2 marker. Finally, we observed that local administrations of UDP in B16-engrafted C57BL6 mice reduced tumor growth and necrotic areas. In addition, UDP-treated tumors showed a higher presence of MHCIIhi tumor-associated macrophage (TAM) and of CD3+CD8+ and CD3+CD4+ tumor-infiltrating T-lymphocytes (TILs), both markers of anti-tumor immune response. Consistent with this, intra-tumoral gene expression analysis revealed in UDP-treated tumors an increase in the expression of genes functionally linked to anti-tumor immune response. Our analysis revealed an important metabolite acting as mediator of immune response, which could potentially represent an additional tool to be used as an adjuvant in cancer immunotherapy.

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“…Targeted metabolic profiling of mouse plasma and xenograft samples was performed using the MxP ® Quant 500 kit combined with the UHPLC-MS/MS-based acylcarnitine assay (Biocrates Life Sciences) as described previously [ 17 ]. In brief, xenograft tissues were homogenized in 85:15 ethanol:0.01 M phosphate lysis buffer at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

“…The predefined pattern “1–2–1–1” used for the Pattern Search corresponds to concentrations of metabolites of the different groups in the following order: “NTM CTRL (1)–melanoma CTRL (2)–melanoma LCT (1)–melanoma LCT-MCT (1)”, while “2” indicates higher metabolite concentrations than “1”. The metabolomics data set of plasma samples from NTM was reported previously [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…Melanoma cells mainly utilize glycolysis to produce ATP; however, they are also able to generate energy via mitochondrial respiration [ 13 – 16 ]. Using metabolic profiling, we recently showed that different human melanoma cells engrafted into mice presented distinct metabolomes that was otherwise independent of the intrinsic driver mutation [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity

et al. 2022

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Background Growing evidence supports the use of low-carbohydrate/high-fat ketogenic diets as an adjunctive cancer therapy. However, it is unclear which genetic, metabolic, or immunological factors contribute to the beneficial effect of ketogenic diets. Therefore, we investigated the effect of ketogenic diets on the progression and metabolism of genetically and metabolically heterogeneous melanoma xenografts, as well as on the development of melanoma metastases in mice with a functional immune system. Methods Mice bearing BRAF mutant, NRAS mutant, and wild-type melanoma xenografts as well as mice bearing highly metastatic melanoma allografts were fed with a control diet or ketogenic diets, differing in their triglyceride composition, to evaluate the effect of ketogenic diets on tumor growth and metastasis. We performed an in-depth targeted metabolomics analysis in plasma and xenografts to elucidate potential antitumor mechanisms in vivo. Results We show that ketogenic diets effectively reduced tumor growth in immunocompromised mice bearing genetically and metabolically heterogeneous human melanoma xenografts. Furthermore, the ketogenic diets exerted a metastasis-reducing effect in the immunocompetent syngeneic melanoma mouse model. Targeted analysis of plasma and tumor metabolomes revealed that ketogenic diets induced distinct changes in amino acid metabolism. Interestingly, ketogenic diets reduced the levels of alpha-amino adipic acid, a biomarker of cancer, in circulation to levels observed in tumor-free mice. Additionally, alpha-amino adipic acid was reduced in xenografts by ketogenic diets. Moreover, the ketogenic diets increased sphingomyelin levels in plasma and the hydroxylation of sphingomyelins and acylcarnitines in tumors. Conclusions Ketogenic diets induced antitumor effects toward melanoma regardless of the tumors´ genetic background, its metabolic signature, and the host immune status. Moreover, ketogenic diets simultaneously affected multiple metabolic pathways to create an unfavorable environment for melanoma cell proliferation, supporting their potential as a complementary nutritional approach to melanoma therapy.

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Targeted Metabolomics Identifies Plasma Biomarkers in Mice with Metabolically Heterogeneous Melanoma Xenografts

Cited by 12 publications

References 79 publications

Serum Amino Acid Profiles Predict the Development of Hepatocellular Carcinoma in Patients with Chronic HBV Infection

Serum Amino Acid Profiles Predict the Development of Hepatocellular Carcinoma in Patients with Chronic HBV Infection

Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor Growth

Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity

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