Abstract 7349: Ligand-receptor signaling analysis and tumor-immune microenvironment deconvolution reveal differential adipose-tumor crosstalk in lean and obese colon cancer patients

Abstract Obesity is a well-defined risk factor for colon cancer (CC). In the current study, we investigated the paracrine influences between tumors and adjacent adipose tissue to understand the interactions between adipose-tumor using transcriptomics data. Stage I-III newly diagnosed CC patients (n = 130) as part of the ColoCare Study at the Huntsman Cancer Institute, University of Utah, and University of Heidelberg, Germany were included in the current study. Fresh-frozen colon tumor tissues and adjacent adipose tissues naïve to neoadjuvant treatment were collected during surgery. RNA sequencing was done using the NovaSeq X. Patients were classified as having a BMI <30 kg∙m−2 (lean) or BMI ≥30 kg∙m−2 (obese). Tumor-adipose signaling was investigated separately for lean versus obese patients. Differentially expressed genes (DEGs, FDRq<0.05 and |log2FC|>2) between paired tumor-adipose samples were identified through DESeq2, respectively for lean and obese participants. DEGs were filtered to obtain exclusively up-regulated genes for 1) tumor tissue in the obese 2) tumor tissue in the lean 3) adipose tissue in the obese 4) adipose tissue in the lean. Ligand-receptor pairs for adipose-adipose signaling (A-A), tumor-tumor signaling (T-T), adipose-tumor signaling (A-T), and tumor-adipose signaling (T-A) in tissues from lean versus obese patients were determined by mapping the exclusively up-regulated genes in the FANTOM 5 database. Single sample Gene Set Enrichment Analysis (ssGSEA) was performed to score each sample based on signatures of interest, i.e. TIMEx immune cell types. The associations of signatures between tumor-adipose were assessed by evaluating Spearman’s correlation coefficients on the enrichment scores of each signature for paired tumor-adipose samples. From RNA-seq, there were 430 protein-coding DEGs (144 up-regulated in the tumor, 286 up-regulated in the adipose) identified exclusively in the obese and; 704 protein-coding DEGs (421 up-regulated in the tumor, 283 up-regulated in the adipose) identified exclusively in the lean patients. In the obese, we observed ligand-receptor-mediated T-T signaling through FGF5-FGFR3 and PYY-NPY4R; T-A signaling through GCG-GCGR; A-A signaling through ICAM1-IL2RA. In the lean, we found ligand-receptor-mediated T-T signaling through ADAM2-ITGA6 and LAMB3-ITGA6; T-A signaling through DLL3-NOTCH2; A-A signaling through DLK1-NOTCH2. In addition, ssGSEA analysis showed different association patterns for the lean versus obese regarding the TIMEx immune cell types. Our results suggest differential cross-talk between adipose and tumor tissue in lean vs. obese patients could influence the progression of CC. The next steps are to validate these interactions by using in vivo preclinical models to interrogate novel therapeutic targets for reducing the impact of obesity on CC. Citation Format: Tengda Lin, Victoria M. Bandera, Elaine M. Glenny, Caroline Himbert, Jennifer Ose, Christy Warby, Olena Aksonova, Alessandro Carpanese, Chris Stubben, David Nix, Kenneth M. Boucher, Peter Schirmacher, Ildiko Strehli, Jolanta Jedrzkiewicz, Courtney L. Scaife, Bartley Pickron, Alexander Brobeil, Martin Schneider, Christoph Kahlert, Erin M. Siegel, Adetunji T. Toriola, David Shibata, Christopher I. Li, Jane C. Figueiredo, Jatin Roper, Biljana Gigic, Stephen D. Hursting, Cornelia M. Ulrich, Aik Choon Tan. Ligand-receptor signaling analysis and tumor-immune microenvironment deconvolution reveal differential adipose-tumor crosstalk in lean and obese colon cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7349.