Abstract 3056: Gut microbial co-metabolism influences the tumor microenvironment
Authors: Paizs Petra , Roberts Duncan , Danckert Nathan , Lewis James , Sani Maria , Jamroziak Marta , Goldin Robert , Marchesi Julian , Ford Lauren , Alexander James , Takats Zoltan , Kinross James 
Published: June 2022

Right sided colorectal cancers (RCRCs) have distinct molecular phenotypes and clinical presentations to those on the left. Gut microbial co-metabolic interactions with the RCRC microenvironment are poorly defined and present a novel therapeutic target. Here, we present a multi-omics analysis of RCRCs.

A prospective observational pilot study was performed at Imperial College London NHS Trust, UK. Treatment naive patients undergoing elective resectional surgery for primary RCRCs were recruited. Fresh intra-luminal fecal samples were obtained at three anatomical sites: 5 cm pre-, tumor, and 5 cm post-tumor. Microsatellite instability (MSI) and CDX2 expression were immunohistochemically evaluated. Metataxonomic analysis was carried out on a MiSeq Platform (Illumina, USA). Metabolomics analysis was performed using liquid chromatography mass spectrometry (Acquity UPLC, Xevo G2-S Q-TOF, Waters). After pre-processing, univariate and multivariate statistics were carried out in MetaboAnalyst and RStudio.

20 patients (8 females, mean age 69.9(53-83)) were included. Of the n=20 RCRCs, n=2 were ileo-cecal valve, n=4 were cecal, n=4 were cecum/proximal ascending colon, n=4 were mid-ascending colon, n=2 were ascending/hepatic flexure, n=2 were hepatic flexure, and n=2 were transverse colon cancers. Tumor classification according to TNM 8 indicated n=4 T1, n=1 T2, n=11 T3, n=4 T4; n=12 as N0, n=6 as N1, and n=2 as N2; n=2 as M0, n=1 as M1c, and n=17 as MX. All n=20 were CDX2 positive and n=16 had normal expression of mismatch repair proteins, n=4 showed MSI. Triglyceride (TG) species were significantly associated with T3-4 rather than T1-2 (p&lt;0.01). Ceramide and diacylglycerol species were significantly associated with T1-2 rather than T3-4 (p&lt;0.01). Multiple TG, an acyl carnitine, and a lysophosphatidic acid (LPA) species were associated with MSI status rather than no MSI status (p&lt;0.01). An integrative analysis pipeline was developed to investigate statistically significant covariance between specific metabolites and taxa (p&lt;0.01). Specifically, Procrustes similarity analysis of the multi-omics dataset revealed a negative correlation at pre- (p=0.606) and tumor level (p=0.738), but significant similarity at post-tumor level (p=0.045). This pattern in post-tumor may indicate cancer specific co-metabolism. At the post-tumor site, the LPA species increased in MSI, showed a negative correlation with members of the Oscillospiraceae family. Ceramide species, significantly increased in early-stage CRC, demonstrate negative correlation with the Lachnospiraceae family. Ongoing work is examining site-matched tissue samples utilizing imaging mass cytometry to define immune interactions.

Mapping the intra-luminal fecal metabolome and metataxonome in RCRC reveals potential bacterial-host co-metabolic targets that could be leveraged for stratifying immunotherapy treatment.

Citation Format: Petra Paizs, Duncan Roberts, Nathan Danckert, James Lewis, Maria Sani, Marta Jamroziak, Robert Goldin, Julian Marchesi, Lauren Ford, James Alexander, Zoltan Takats, James Kinross. Gut microbial co-metabolism influences the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3056.