Understanding the role of lipid metabolism in colorectal cancer reveals a path to therapies that could turn chronic inflammation into an opportunity for cancer resolution.
Study: Integration of lipidomics with targeted, single cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer. Image Credit: Vladimir Sukhachev / Shutterstock
In a recent study published in the journal Gut, scientists investigated the lipid metabolism disruptions in colorectal cancer, focusing on the imbalance between pro-inflammatory and inflammation-resolving lipid mediators. The researchers integrated lipidomics with advanced molecular and spatial transcriptomics to explore the mechanisms of inflammation persistence in the tumor microenvironment and proposed novel therapeutic strategies to address these disruptions.
Background
Colorectal cancer is among the most prevalent cancers globally and a leading cause of cancer-related mortality. Chronic inflammation is a recognized factor in colorectal cancer progression and is often attributed to an imbalance between pro-inflammatory and inflammation-resolving or pro-resolving processes.
In normal wound healing, a process known as lipid mediator class switching results in inflammation transitioning to resolution, which also involves molecules such as lipoxins and resolvins. However, colorectal cancer appears to exhibit impaired class switching, resulting in sustained inflammation. Furthermore, lipids play critical roles in cell signaling, energy storage, and structural functions, and dysregulated lipid metabolism can significantly influence tumor progression.
Previous studies have highlighted the unique lipidomic profiles seen in colorectal cancer, noting their correlation with both disease stage and outcomes. The impact of dietary factors, such as omega-6 and omega-3 fatty acids, on colorectal cancer further emphasizes its metabolic complexity. However, the understanding of the molecular mechanisms linking lipid metabolism to the tumor microenvironment in colorectal cancer remains limited.
About the Study
In the current study, the team employed a multi-modal approach to examine lipid metabolism in colorectal cancer using 81 paired tumor and normal tissue samples. The untargeted lipidomics analysis focused on 40 paired samples, while the targeted lipidomics assessed arachidonic acid (AA) pathway-related mediators. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was utilized for both untargeted and targeted lipidomics analyses.
Untargeted lipid profiling was used to analyze 40 sample pairs and identify the major differences in lipid species, while the targeted analyses measured specific lipid mediators associated with the arachidonic acid (AA) pathway, which has been linked to cancer progression.
The study also included spatial transcriptomics to map the gene expression of lipid metabolism-related enzymes in colorectal cancer tissues. Additionally, the researchers used quantitative reverse transcription polymerase chain reaction (qRT-PCR) and publicly available single-cell ribonucleic acid (RNA) sequencing datasets to support the findings.
Furthermore, specific enzymes involved in lipid class switching, such as arachidonate 5-lipoxygenase (ALOX5) and arachidonate 15-lipoxygenase (ALOX15), were analyzed for their expression and co-localization. The study also used spatial analysis to identify tumor-associated macrophages (TAMs), which were shown to be the primary producers of pro-inflammatory lipid mediators.
The tumor and normal tissues were matched and collected from diverse colorectal cancer stages and locations, and immunohistochemical analyses were conducted to verify that no malignancy was present in the normal tissue samples.
Furthermore, the researchers used advanced statistical tools to interpret lipidomic and transcriptomic data, including heatmaps and Spearman correlation analysis, to identify the patterns linked to pro-inflammatory and resolving lipid mediators. The findings were then cross-validated using large-scale gene expression datasets from independent colorectal cancer cohorts.
Major Findings
The study found that colorectal cancer tissues exhibit a significant pro-inflammatory lipid profile compared to normal tissues. The quantitative lipidomics analysis identified elevated levels of AA-derived mediators, including leukotrienes and 5-hydroxyeicosatetraenoic acid (5-HETE), associated with the enzyme ALOX5. Conversely, pro-resolving mediators such as lipoxins were markedly deficient, indicating defects in lipid mediator class switching.
Gene expression analysis also revealed the overexpression of pro-inflammatory genes in colorectal cancer tissues, such as ALOX5, ALOX5 activating protein (ALOX5AP), and leukotriene-A4 hydrolase (LTA4H). These genes correlated strongly with inflammatory biomarkers and macrophage markers, emphasizing the role of TAMs in sustaining inflammation. Furthermore, the spatial transcriptomics results highlighted the co-localization of pro-inflammatory enzymes in high leukotriene-producing tumors.
The researchers observed the reduced expression of enzymes responsible for synthesizing resolving mediators, including ALOX12 and ALOX15, across all samples. Prostaglandin levels—prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2)—were found to be significantly lower in most colorectal cancer tumors, which the study attributed to low expression of their synthesizing enzymes.
Additionally, the lipidomic profiling revealed specific structural lipid changes, including the enrichment of phospholipids containing linoleic acid and AA. These alterations also correlated with chronic inflammation and tumor progression, indicating metabolic disruptions in the tumor microenvironment.
Importantly, the researchers found that colorectal cancer tumors displayed immune subtypes characterized by distinct lipid mediator patterns. Pro-inflammatory lipid dominance was especially prominent in tumors with immune activation or inflammation, linking lipid metabolism to immune status. These findings provided evidence that colorectal cancer progression is driven by a persistent inflammatory state arising from disrupted lipid metabolism.
Conclusions
Overall, the findings emphasized the pivotal role of lipid metabolism in sustaining inflammation within colorectal cancer. A marked imbalance between pro-inflammatory and inflammation-resolving mediators was found to underlie the persistent inflammatory state in colorectal cancer. By identifying these key molecular and cellular mechanisms, the study offered insights into potential therapeutic strategies that could focus on restoring lipid class switching through endogenous or exogenous pro-resolving mediators.
Journal reference:
- Soundararajan, R., Maurin, M. M., Rodriguez-Silva, J., Upadhyay, G., Alden, A. J., Gowda, S. B., Schell, M. J., Yang, M., Levine, N. J., Gowda, D., Sundaraswamy, P. M., Hui, S., Pflieger, L., Wang, H., Marcet, J., Martinez, C., Bennett, R. D., Chudzinski, A., Karachristos, A., & Nywening, T. M. (2024). Integration of lipidomics with targeted, single-cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer. Gut, gutjnl2024332535. DOI:10.1136/gutjnl2024332535 https://gut.bmj.com/content/early/2024/11/26/gutjnl-2024-332535