Abstract 161: High-resolution spatial proteomics characterizes colorectal cancer consensus molecular subtypes

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Abstract Background: Identification of the consensus molecular subtypes (CMS) opened significant potential for understanding the tumor biology and intertumoral heterogeneity of colorectal cancer (CRC). Molecular subtyping in CRC traditionally relies on bulk transcriptomics. However, single-cell transcriptomics studies have shown that CRC tumors may be composed of tumor cells displaying different CMS traits, suggesting additional intratumoral heterogeneity. Methods: To investigate intratumoral heterogeneity at protein level, we constructed tissue microarrays using tumor cores from 222 CRC patients. Arrays were stained and imaged with Cell DIVE multiplexed immunofluorescence (MxIF) imaging using 54 selected protein markers, ranging from cell identity markers to cancer hallmark proteins of metabolism, proliferation, cell death and differentiation. RNA sequencing data and CMS classification were also available for all patients. After segmentation of tumor, stromal and immune cells, we investigated intratumoral heterogeneity within CMS subtypes using spatially resolved single-cell protein profiling (>2 million cells). We compared cell types, their spatial organization and their expression of cancer hallmark-related proteins in CMS 1-4 subtypes. Results: We revealed tissue atlases illustrating the cell types/states, spatial heterogeneity, cellular neighborhoods, cellular network, and single-cell protein profiles of CMS tumors. CMS1 tumors had more CD3+, CD8+, and PD1+ immune cells that were found in the epithelial layer more frequently than in the other subtypes. CMS1 was also associated with higher levels of metabolic reprogramming markers such as upregulated glycolysis. CMS2 showed immune segregation, reactive stroma patterns, and higher levels of apoptotic and proliferative signaling proteins. CMS3 exhibited tightly clustered cancer cells with high RIP3 and low FLIP levels, suggesting a pro-inflammatory microenvironment driven by intense cell-cell interactions and stromal hubs. CMS4 displayed stromal-centric and immune-evasive tumors characterized by decreased HLA-1 levels and regulatory T cell exclusion from epithelium. Conclusion: We present the first spatial atlas of CRC tumors with regard to their molecular subtypes at single-cell protein resolution and demonstrate new spatial aspects of tumor structures in CRC. Citation Format: Batuhan Kisakol, Anna Matveeva, Sanghee Cho, Mohammedreza Azimi, Andreas U. Lindner, Manuela Salvucci, Elizabeth McDonough, Joanna Fay, Tony O'Grady, Niamh McCawley, John P. Burke, Deborah McNamara, John Graf, Simon McDade, Daniel B. Longley, Fiona Ginty, Jochen H. Prehn. High-resolution spatial proteomics characterizes colorectal cancer consensus molecular subtypes [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 161.

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