Abstract 2076: Spatiotemporal mapping of colitis-associated colorectal cancer evolution

Abstract Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease, particularly ulcerative colitis. Despite its clinical significance, the spatiotemporal dynamics of neoplastic progression in CAC remain poorly understood. This study aimed to elucidate the evolutionary trajectory of CAC using spatial transcriptomics. We employed spatial transcriptomics to analyze four tissue samples from three patients with ulcerative colitis at various stages of neoplastic progression. Whole-slide spatial transcriptomics RNA sequencing was performed, enabling simultaneous analysis of gene expression and tissue architecture. Integrated spatial transcriptomic data revealed recurring epithelial programs along the progression of copy number variation (CNV). Our analysis using CNV score and hematoxylin and eosin staining image revealed progressive changes in gene expression patterns as tissue transitioned from non-tumor to pre-tumor and finally to tumor states. This progression was quantified using beta coefficient values, allowing us to track gradual alterations in gene expression across the disease continuum. We identified a core set of 412 genes that exhibited consistent changes in at least three of the analyzed samples. Among these, 349 genes showed a progressive decrease in expression, while 63 genes, including CLDN1, E2F1, and RECQL4, demonstrated a gradual increase in expression as the tissue advanced towards a tumorous state. These upregulated genes pointed to potential oncogenic drivers or compensatory mechanisms activated during tumor development. Pathway analysis revealed that downregulated genes were enriched in processes such as KRAS signaling, hypoxia, and inflammatory response, while upregulated genes were enriched in the MYC targets pathway. This study provides high-resolution mapping of evolutionary trajectory of CRC, revealing key molecular events and spatial features associated with neoplastic progression. Our findings enhance the understanding of CAC pathogenesis and highlight potential targets for early intervention and personalized treatment strategies, contributing significantly to the field and potentially informing future therapeutic approaches. Citation Format: Yoonho Lee, Yongjae Kim, Minseok Lee, Do Kyung Yoon, Jiwon Baek, Sung Wook Hwang, Jong Lyul Lee, Sang Hyoung Park, Dong-Hoon Yang, Jihun Kim, Suk-Kyun Yang, Buhm Han, Kyuyoung Song, Yong Sik Yoon, Byong Duk Ye, Ho-Su Lee. Spatiotemporal mapping of colitis-associated colorectal cancer evolution. [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 2076.