Stromal THY1 expression is associated with improved survival in low-stroma colorectal cancer: an integrated multi-platform analysis

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Abstract Background Colorectal cancer (CRC) remains a global health challenge. The tumor microenvironment (TME) plays an important role in CRC progression, yet the cellular distribution and prognostic significance of stromal THY1 (CD90) remain incompletely understood. Methods We investigated THY1 expression in the CRC microenvironment using a multi-platform approach integrating publicly available bulk and single-cell transcriptomic datasets, a transgenic mouse model with ex vivo tissue imaging and histological assessment, and immunohistochemical (IHC) analysis of a retrospective human stage II-III CRC cohort (n = 274; n = 264 with complete survival data). Results THY1 was not detected by IHC in non-neoplastic colorectal mucosa and was predominantly observed in stromal and vascular compartments in colorectal neoplastic tissues. Single-cell RNA sequencing showed that THY1 expression was mainly localized to fibroblast/CAF, pericyte, and endothelial populations. In the overall survival cohort, high stromal THY1 expression ( H- score > 150) was associated with longer relapse-free survival (RFS) (HR = 0.64, 95% CI: 0.42-0.96, p = 0.03). In the exploratory ≤ 20% stroma subgroup, high THY1 expression was associated with longer overall survival (OS) (HR = 0.21, 95% CI: 0.10-0.46, p = 0.002) and RFS (HR = 0.29, 95% CI: 0.15-0.61, p = 0.005). However, stromal THY1 expression was not independently associated with OS or RFS in the multivariate models. In the reporter mouse experiment, YFP signal was detected in brain tissue, whereas no prominent reporter signal was detected in the gastrointestinal tract or intestinal lesions under the imaging conditions used. Conclusions Stromal THY1 expression was associated with favorable survival outcomes in this stage II-III CRC cohort, particularly in exploratory analyses of tumors with low stromal content. These findings are hypothesis-generating and require validation in independent cohorts.