Abstract 5249: Crosstalk between visceral adipose and tumor tissue in colorectal cancer patients: Molecular signals driving host-tumor interaction

Abstract

Abstract Adipose tissue has recently emerged as a driver of tumorigenesis, as adipose-associated factors enhance tumor growth and development. Here we investigated for the first time direct crosstalk between visceral adipose tissue (VAT) and tumor tissues in colorectal cancer (CRC) patients. We analyzed paired transcriptomic profiles of tissues and systemic inflammatory biomarkers among CRC patients to elucidate potential mechanisms and molecular signals driving the host-tumor interaction. Paired presurgery blood and tumor adjacent VAT, colorectal tumor and mucosa tissue samples collected during surgery were obtained from 47 Caucasian patients diagnosed with microsatellite-stable primary CRC enrolled in the ColoCare Study. Clinical/demographic information, and lifestyle-related risk factors, were reported. VAT was quantified by computed tomography. RNA was extracted from VAT, colorectal tumor and mucosa tissues, analyzed using HumanHT-12 Expression BeadChips, processed, and validated. Serum-based assays were conducted in 46 of 47 patients for systemic inflammatory markers with the Mesoscale Discovery Platform. High PTGS2 tumor expression was associated with 131 significantly altered VAT genes, of which 85.5% were upregulated. A significant upstream regulator of dysregulated VAT genes was SAA1. Investigation of circulating inflammatory biomarkers corroborated these transcriptomic findings, as patients with high PTGS2 tumor expression were also significantly more likely to have higher serum-based SAA levels. The differential expression of PPAR-γ in VAT identified 284 significantly altered tumor genes. 71.8% of tumor genes were upregulated in association with higher PPAR-γ VAT expression. Differentially expressed tumor genes were enriched in functional cellular movement. Inflammatory biomarkers in patient sera showed marginally significant differences for soluble ICAM-1 in association with differential PPAR-γ VAT expression. Overlap of the 131 altered VAT genes associated with differential PTGS2 tumor expression with the 284 dysregulated tumor genes associated with differential PPAR-γ VAT expression identified 15 common genes. Gene set enrichment analysis demonstrated that phenotypes associated with these genes in humans included cancer invasiveness signatures from tumor microenvironment interactions. Our multi-omics profiling of paired tissue transcriptomics and systemic inflammatory biomarkers from CRC patients established a bidirectional link between VAT and colorectal tumor tissue. We have demonstrated that this direct crosstalk activates signaling cascades to promote proinflammatory interactions and metabolic reprogramming. Future efforts to develop mechanism-based interventions that disrupt these molecular signals at the nexus of VAT-tumor crosstalk may improve obesity-driven CRC prevention and control. Citation Format: Andreana N. Holowatyj, Mariam Haffa, Tengda Lin, Biljana Gigic, Jennifer Ose, Christy Warby, Caroline Himbert, Clare Abbenhardt, Juergen Boehm, Magnus von Knebel Doeberitz, Nina Habermann, Esther Herpel, Hans-Ulrich Kauczor, Matthias Kloor, Johanna Nattenmüller, Peter Schirmacher, Martin Schneider, Petra Schrotz-King, Thomas Simon, Alexis Ulrich, Laura Bowers, Stephen D. Hursting, Cornelia M. Ulrich. Crosstalk between visceral adipose and tumor tissue in colorectal cancer patients: Molecular signals driving host-tumor interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5249.