Lysosome-dependent cell death reveals a prognostic signature in colorectal cancer via integrated analysis of scRNA-seq and bulk RNA-seq data.

BACKGROUND

Colorectal cancer (CRC) is one of the most common vulgar malignancies worldwide. Recent researches have displayed that lysosomes, important intracellular degradation and signal transduction centers, dramatically affect cancer occurrence and development via regulating proliferation, metabolism, programmed death and other key biological processes. Lysosomes significantly influence CRC progression by regulating biological processes such as programmed cell death. This study aims to develop a lysosome-dependent cell death (LDCD)-based prognostic signature to predict survival and immunotherapy efficacy in CRC patients.

METHODS

In our work, we innovatively incorporated single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) data to establish an LDCD activity evaluation system and systematically analyzed the dynamic changes in LDCD activity during the differentiation trajectory of tumor cells and its interaction with tumor microenvironment (TME).

RESULTS

We observed that high-LDCD-producing tumor cells were present mainly in the initial stage of CRC differentiation via single-cell trajectory analysis. Further cell communication network analysis revealed significantly different interaction patterns between tumor cell subsets with different LDCD activities and TME components. A prognostic signature composed of key LDCD-pertaining genes was constructed based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) multicenter cohort data. Validation analysis indicated that the prognostic signature effectively stratified patients into different risk groups, and high- and low-risk groups presented huge disparities in overall survival, immune microenvironment characteristics, treatment sensitivity and immunotherapy response.

CONCLUSIONS

This study characterizes the spatiotemporal heterogeneity of LDCD activity in CRC from a single-cell perspective. The identified prognostic markers act as independent clinical indicators and furnish a critical theoretical foundation and potential therapeutic targets for advancing personalized CRC management.