Abstract 6263: Multi-transcriptomic analysis reveals tumor microenvironment differences associated with anti-EGFR therapy responsiveness between left- and right-sided colorectal cancer

Abstract Background: Regarding the sidedness of colorectal cancer, right-sided colorectal cancer (RCRC) and left-sided colorectal cancer (LCRC) originate from the midgut and hindgut, respectively. It is known that in stages III and IV, RCRC has a poorer prognosis compared to LCRC. Furthermore, the prognosis of colorectal liver metastasis (CRLM) also varies depending on the primary tumor's sidedness. Although differences such as MSI-H status, BRAF mutations, and histological types have been noted between right- and left-sided colorectal cancers, clinical observations have recognized that differences in treatment efficacy exist even when these factors are excluded. This study aimed to compare left- and right-sided colorectal cancers based on their responsiveness to anti-EGFR therapy and to elucidate differences in cancer cells and the tumor microenvironment (TME). Methods: We collected microsatellite stable (MSS) and BRAF mutation-negative cases from six scRNA-seq cohorts, integrating data from 28 right-sided and 57 left-sided cases. Specifically, on the left side, only KRAS wild-type cases that respond to anti-EGFR inhibitors were included. Cancer cells were extracted from the integrated data, and differences in the therapeutic effects of anti-EGFR drugs were analyzed. Subsequently, focusing on cancer-associated fibroblasts (CAFs) that strongly interact with cancer cells, we analyzed differences in cell-cell communication within the TME. Results: After extracting cancer cells and performing pseudobulk analysis and PCA, significant differences were observed between cancer cells of left-sided and right-sided colorectal cancers. Furthermore, evaluation of copy number variations (CNVs) using inferCNV revealed that left-sided colorectal cancers exhibit higher chromosomal instability (CIN). In analyses related to responsiveness to anti-EGFR therapy, it was confirmed that the expression of EREG (epiregulin), one of the EGFR ligands, was significantly higher in left-sided colorectal cancers. Additionally, focusing on cell-cell communication within the TME mediated by EREG, we found that only cancer cells of left-sided colorectal cancer interact with fibroblasts—especially inflammatory CAFs (iCAFs)—through the EGF pathway. Conclusion: This study identifies key differences in tumor cell characteristics and the TME between RCRC and LCRC. The higher responsiveness of LCRC to anti-EGFR therapy may be attributed to intrinsic features such as elevated EREG expression and CIN, as well as enhanced interactions with fibroblasts via the EGF pathway. These findings provide insights into the mechanisms underlying the differential efficacy of anti-EGFR therapy based on tumor sidedness. Citation Format: Atsuki Taniguchi, Shunsuke Kagawa, Shohei Nogi, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Satoru Kikuchi, Shinji Kuroda, Hiroshi Tazawa, Toshiyoshi Fujiwara. Multi-transcriptomic analysis reveals tumor microenvironment differences associated with anti-EGFR therapy responsiveness between left- and right-sided colorectal cancer [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 6263.