Dataset Information

Spatial and Untargeted Metabolomics Define Location- and Histology-Specific Metabolic Reprogramming in Colorectal Cancer

ABSTRACT:

Colorectal cancer (CRC) exhibits profound molecular heterogeneity based on primary tumor location. A comprehensive understanding of the spatially resolved metabolic differences between right-sided (RCC) and left-sided (LCC) carcinomas remains elusive. Here, to eliminate the influence of inter-individual heterogeneity on metabolic differences, we performed spatial metabolomics using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) on synchronous bilateral tumors from the same patient. This was complemented by untargeted metabolomic profiling via ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) on tumor and matched normal tissues from 30 CRC patients with different locations and histologies. Our analysis identified 345 metabolites and revealed distinct, location-specific metabolic reprogramming. Among these, 72 altered metabolites between left- (Ltu) and right-sided colon tubular adenocarcinomas (Rtu) indicated disruptions in ether lipid and phosphatidylcholine metabolism of Ltu and nucleotide, amino sugar, and fatty acid metabolism of Rtu. Furthermore, right-sided mucinous adenocarcinomas (Rmu) were characterized by unique sphingolipid metabolism reprogramming, shifting from an 'apoptosis-promoting signaling' to a 'structural construction' function, compared to Rtu. N-Acetylneuraminic acid, oleoyl-l-carnitine and 12-Hydroxystearic acid are representative DEMs in the aforementioned pathway. Spatial analysis delineated metabolic profiles varied spatially from the tumor center to the periphery. Collectively, our findings underscore the influence of primary tumor location on metabolism and suggest subtype-specific metabolic adaptation mechanisms associated with histology and spatial architecture.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - positive - reverse-phase, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS13729 | MetaboLights | 2026-03-24

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13729_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS13729_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13729_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	a_MTBLS13729_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt

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Project description:Alterations in glycosylation are seen in many types of cancer, including colorectal cancer (CRC). CRC is known to display glycosylation alterations. Glycans, the sugar moieties of glycoconjugates, are involved in many important functions relevant to cancer, such as cell signaling and adhesion, and may can be of value as biomarkers. In this study, we have used mass spectrometry to analyze the N-glycan profiles of 35 CRC tissue samples from patients with tumors in the right or left colon and 10 healthy tissue samples from non-CRC patients who underwent operations for other reasons. The tumor samples were divided into groups depending on tumor location (right or left colon) and stage (II or III), while the healthy samples were divided into right or left side of the colon. The levels of neutral and acidic N-glycan compositions and glycan classes were analyzed in a total of ten different groups. Surprisingly, there were no significant differences in glycan levels when all right- and left-sided CRC samples were compared, and few differences (such as in the abundance of the neutral N-glycan H3N5) were seen when the samples were divided according to both location and stage. Multiple significant differences were found in the levels of glycans and glycan classes when stage II and III samples were compared, and these glycans could be of value as candidates for new markers of cancer progression. In order to validate our findings, we analyzed healthy tissue samples from the right and left colon and found no significant differences in the levels of any of the glycans analyzed, confirming that our findings when comparing CRC samples from the right and left colon are not due to normal variations in the levels of glycans between the healthy right and left colon. Additionally, the levels of the acidic glycans H4N3F1P1, H5N4F1P1, and S1H5N4F1 were found to change in a cancer-specific but colon location-nonspecific manner, indicating that CRC affects glycan levels in similar ways, regardless of tumor location.

Project description:BACKGROUND: Studies have reported clinical heterogeneity between right-sided colon cancer (RCC) and left-sided colon cancer (LCC). However, none of these studies used multi-omics analysis combining genetic regulation, microbiota and metabolites to explain the site-specific difference.METHODS: Here, 494 participants from a 16S rRNA gene sequencing cohort (50 RCC, 114 LCC and 100 healthy controls) and a multi-omics cohort (63 RCC, 79 LCC and 88 healthy controls) were analyzed. 16S rRNA gene, metagenomic sequencing and metabolomics analyses of fecal samples were evaluated to identify tumor location-related bacteria and metabolites. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-seq) were conducted to obtain the mutation burden and genomic expression pattern.RESULTS: We found unique profiles of the intestinal microbiome, metabolome, and host genome between RCC and LCC. The bacteria Flavonifractor plautii (Fp) and Fusobacterium nucleatum, the metabolites L-phenylalanine, and the host genes PHLDA1 and WBP1 were the key omics features of RCC; whereas the bacteria Bacteroides sp. A1C1 (B.A1C1) and Parvimonas micra, the metabolites L-citrulline and D-ornithine, and the host genes TCF25 and HLA-DRB5 were considered the dominant omics features in LCC. Multi-omics correlation analysis indicated that RCC-enriched Fp was related to the accumulation of the metabolite L-phenylalanine and the suppressed WBP1 signal in RCC patients. In addition, LCC-enriched B.A1C1 was associated with accumulation of the metabolites D-ornithine and L-citrulline as well as activation of the genes TCF25, HLA-DRB5 and AC079354.1.CONCLUSION: Our findings identify previously unknown links between intestinal microbiota alterations, metabolites and host genomics in RCC vs. LCC, suggesting that it may be possible to treat colorectal cancer (CRC) by targeting the gut microbiota-host interaction.

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Spatial and Untargeted Metabolomics Define Location- and Histology-Specific Metabolic Reprogramming in Colorectal Cancer

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