Abstract 774: Deciphering the biology of colorectal metastasis to the peritoneal surface

Abstract Background. Colorectal cancer (CRC) is the third most frequently diagnosed cancer with an annual incidence of 1.4 million new cases and 700, 000 deaths worldwide. The high death toll of CRC patients is due to metastatic disease with liver being the preferred site of metastasis (LM), followed by lung and peritoneal metastasis (PM). Roughly 25% of CRC patients present with, or will eventually develop PM, and while survival for LM and lung metastasis has significantly improved over time, survival following PM remains poor. Mucinous and non-mucinous adenocarcinoma have different propensity to form PM or LM, and surprisingly little is known about the biology of CRC PM. Aims and Objectives. To perform deep mapping using Nanostring’s GeoMx Cancer Transcriptome Atlas assay to measure gene expression in resected normal colon (healthy) primary tumors (primary), LM, and PM samples collected from the KUMC Biospecimen Repository. Morphological staining using Pan-cytokeratin, CD45, & ELA2 was performed to identify epithelial tumor cells, immune cells, and neutrophils, respectively. Data processing and resulting DCC files were imported to the GeoMx DSP software for statistical analyses of the transcriptomic data using a linear mixed model. Results. We performed spatial transcriptomic analysis on paired tissue samples (surgical tissue from primary and metastatic sites) from 4 patients with stage IV CRC. Our results unveiled diverse gene expression patterns across different PM and LM tumor sub-regions. Cluster analysis revealed significant differences in gene expression between specimen types. Specifically, in mucinous adenocarcinoma samples, PKM, CEACAM6 and LYZ were upregulated in primary tumors while ADH1A/B/C, Muc4 and PCK1 were upregulated in healthy tissues. Interestingly, we also observed significant upregulation of CEACAM6 and SERPINA1 in PM vs primary tumor cells. In non-mucinous adenocarcinoma, CEACAM6 and H3C2/10 were upregulated in primary vs metastatic tissues. When comparing either primary or metastatic vs healthy stromal areas, COL1A1 and COL6A3 were significantly upregulated in primary and or metastatic regions hinting at extracellular matrix remodeling during PM. In LM, CEACAM6, SLC1A5 and CD74 were significantly upregulated when compared to PM, indicating an inflammatory role in LM. As neutrophil extracellular traps (NETs) promote metastasis, we discovered significant infiltration of ELA2+ neutrophils in the primary mucinous adenocarcinoma while ELA2+ cells were predominantly localized at the leading edge of the non-mucinous adenocarcinoma. These spatio-temporal relationships were further validated in the metastatic sites of the two CRC subtypes. Conclusions. Mucinous vs non-mucinous adenocarcinomas differ in terms of their proclivity to metastasize to the peritoneal surfaces and that the differences could be attributed to the intra-tumoral vs leading edge distribution of ELA2+ neutrophils. Citation Format: Shahid Umar, Badal C. Roy, Amrita Mitra, Jill Haley, Harsh B. Pathak, Andrew K. Godwin, Luke V. Selby, Mazin Al-Kasspooles. Deciphering the biology of colorectal metastasis to the peritoneal surface [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 774.