RCC1 Domain-Containing Protein 1 Promotes Colon Cancer Malignant Progression by Activating Autophagy-Dependent WNT5A Secretion in Cancer-Associated Fibroblasts.

Background

Autophagy plays a dual role in colon cancer, but its mechanisms in tumor-stroma interactions are unclear.

Methods

Using TCGA-COAD and GSE161277 datasets, we identified autophagy-related prognostic genes via bioinformatics and machine learning. RCCD1's role was further investigated using single-cell RNA-seq and functional coculture assays (fibroblasts/HCT116 cells), validated in clinical samples.

Results

RCCD1 was upregulated in colon cancer and cancer-associated fibroblasts (CAFs), correlating with poor prognosis. In CAFs, RCCD1 activated AMPK/mTOR/ULK1 signaling, enhancing autophagy and driving WNT5A secretion. This activated the Wnt/CaMKII/ERK pathway in tumor cells, promoting EMT, proliferation, and invasion. These effects were reversed by autophagy inhibition or WNT5A neutralization.

Conclusion

The RCCD1-autophagy-WNT5A axis is a critical mediator of protumorigenic CAF-tumor cell crosstalk, representing a novel therapeutic target for colon cancer.