Integration of lipidomics with targeted, single cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer

Date:	March 6, 2025
PMID:	PMC11885055
Category:	N/A
Authors:	Ramani Soundararajan, Michelle M Maurin, Jetsen Rodriguez-Silva, Gunjan Upadhyay, Ashley J Alden, Siddabasave Gowda B Gowda, Michael J Schell, Mingli Yang, Noah Jhad Levine, Divyavani Gowda, Punith M Sundaraswamy, Shu-Ping Hui, Lance Pflieger, Heiman Wang, Jorge Marcet, Carolina Martinez, Robert David Bennett, Allen Chudzinski, Andreas Karachristos, Timothy M Nywening, Paul M Cavallaro, Matthew Linley Anderson, Robert J Coffey, Michael V Nebozhyn, Andrey Loboda, Domenico Coppola, Warren Jackson Pledger, Ganesh V Halade, Timothy J Yeatman
Abstract:	39658263

Background: Over a century ago, Virchow proposed that cancer represents a chronically inflamed, poorly healing wound. Normal wound healing is represented by a transitory phase of inflammation, followed by a pro-resolution phase, with prostaglandin (PGE2/PGD2)-induced 'lipid class switching' producing inflammation-quenching lipoxins (LXA4, LXB4).

Objective: We explored if lipid dysregulation in colorectal cancers (CRCs) is driven by a failure to resolve inflammation.

Design: We performed liquid chromatography and tandem mass spectrometry (LC-MS/MS) untargeted analysis of 40 human CRC and normal paired samples and targeted, quantitative analysis of 81 human CRC and normal paired samples. We integrated analysis of lipidomics, quantitative reverse transcription-PCR, large scale gene expression, and spatial transcriptomics with public scRNASEQ data to characterize pattern, expression and cellular localisation of genes that produce and modify lipid mediators.

Results: Targeted, quantitative LC-MS/MS demonstrated a marked imbalance of pro-inflammatory mediators, with a dearth of resolving lipid mediators. In tumours, we observed prominent over-expression of arachidonic acid derivatives, the genes encoding their synthetic enzymes and receptors, but poor expression of genes producing pro-resolving synthetic enzymes and resultant lipoxins (LXA4, LXB4) and associated receptors. These results indicate that CRC is the product of defective lipid class switching likely related to inadequate or ineffective levels of PGE2/PGD2.

Conclusion: We show that the lipidomic profile of CRC tumours exhibits a distinct pro-inflammatory bias with a deficiency of endogenous resolving mediators secondary to defective lipid class switching. These observations pave the way for 'resolution medicine', a novel therapeutic approach for inducing or providing resolvins to mitigate the chronic inflammation driving cancer growth and progression.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center