Single-cell transcriptome highlights a multilayer regulatory network on an invasive trajectory within colorectal cancer progression.

PURPOSE

Colorectal cancer (CRC) is one of the most common and fatal gastrointestinal malignancies, in which cancer stem cells (CSCs) were identified to enable tumor heterogeneity and initiate tumor formation. However, the process from CSCs to invasion cells is unconfirmed.

METHODS

Several bioinformatics methods, including clustering, pseudotime analysis, gene set variation analysis and gene ontology enrichment, were used to construct a path of gradual transformation of CSCs to invasive cells, called "stem-to-invasion path". A large amount of signaling interactions were collated to build the multilayer regulatory network. Kaplan-Meier curve and time-dependent ROC method were applied to reveal prognostic values.

RESULTS

We validated the heterogeneity of cells in the tumor microenvironment and revealed the presence of malignant epithelial cells with high invasive potential within primary colonic carcinomas. Next, the "stem-to-invasion path" was identified through constructing a branching trajectory with cancer cells arranged in order. A multilayer regulatory network considered as the vital factor involved in acquiring invasion characteristics underlying the path was built to elucidate the interactions between tumor cell and tumor-associated microenvironment. Then we further identified a novel combinatorial biomarker that can be used to assess the prognosis for CRC patients, and validated its predictive robustness on the independent dataset.

CONCLUSION

Our work provides new insights into the acquisition of invasive potential in primary tumor cells, as well as potential therapeutic targets for CRC invasiveness, which may be useful for the cancer research and clinical treatment.