Single-cell Transcriptome Profiling of Post-treatment and Treatment-naïve Colorectal Cancer: Insights into Putative Mechanisms of Chemoresistance

Abstract

Drug resistance remains a major clinical challenge in the treatment of colorectal cancer (CRC) with conventional chemotherapy. Analyzing changes within tumor cells and tumor microenvironment (TME) after treatment and in metastases is essential to understanding how resistance develops. In this study, we analyzed scRNA-seq data from 56 CRCs including treatment-naive tumors and tumors treated with standard chemotherapy with the known response status (18 responders and 6 progressors). In our cohort primary left-sided CRCs were associated with metastatic potential mesenchymal phenotype and with depleted B cells. In the post-treatment CRC there was a high prevalence of dendritic cells (DC) in the TME in the response group. The DC-derived signature was associated with better survival in a large CRC cohort from the TCGA. In progressors there was an enrichment of pericyte-like fibroblasts which appeared to be associated with poor survival in a CRC-TCGA cohort. Progressors also showed elevated fractions of exhausted CD8+ T memory cells suggesting a pro-inflammatory TME. In tumor cells of progressors group we identified specific expression of chemo-protective markers MTRNR2L1 and CDX1; and their co-expression with stemness-related immune-checkpoint CD24. In summary, scRNA-seq provides a valuable information for the discovery of prognostic markers, and reveals distinct features potentially underlying response to chemotherapy or disease progression in CRC.