TMEM184A promotes progression and drug resistance in colorectal cancer: a bioinformatics and clinical study

The cellular origin and molecular mechanisms underlying therapeutic resistance in colorectal cancer remain largely unclear.This study integrates single-cell transcriptomics, spatial transcriptomics, molecular docking, and multi-cohort public databases to systematically elucidate the epithelial cell-driven drug resistance mechanism, and combines clinical pathological paraffin samples to evaluate the clinical significance and prognosis of the key protein TMEM184A. Integrated single-cell datasets underwent quality control and PCA/UMAP clustering, followed by annotation verified through spatial transcriptomic mapping. CellChat, CopyKat, inferCNV, Monocle3 and AUCell analyses were applied to assess cell–cell communication, CNV heterogeneity and pseudotime differentiation. Integrate the TCGA, GEO data, as well as the drug sensitivity data from GSCA and CTR-DB 2.0, and combine with the AutoDock molecular docking results to explore the correlation between genes and prognosis, as well as immune infiltration, and their pharmacological effects. Use the tissue microarray technique to detect the protein expression of TMEM184A in cancer tissues and adjacent tissues, and analyze its association with clinical pathological features and patient prognosis. The study identified a subset of epithelial cells associated with drug resistance, characterized by the enrichment of interferon, TNF-α/NF-κB, TGF-β, hypoxia, and p53 signaling pathways.By combining machine learning and clinical prognosis analysis, the key drug-resistant driving gene TMEM184A was finally determined. The genes related to TMEM184A were significantly enriched in the lipid metabolism pathway. Moreover, TMEM184A were highly expressed in microsatellite stable colorectal cancer, positively correlated with regulatory T cell (Treg) infiltration, and associated with the “low immune - low stroma” microenvironment. The analysis of immunohistochemical staining on tissue microarrays showed that the high expression of TMEM184A protein was related to lymph node metastasis, and was more prevalent in the rectal region. Additionally, the high expression of TMEM184A was associated with poor prognosis in patients. Drug sensitivity and molecular docking analysis indicated that TMEM184A had strong binding affinity with lapatinib and various EGFR tyrosine kinase inhibitors. TMEM184A promotes the occurrence of drug resistance in colorectal cancer by regulating lipid metabolism. The high expression of this protein in the rectum is more common and is associated with lymph node metastasis and poor prognosis in patients with colorectal cancer. This study provides a theoretical basis for TMEM184A to be used as a prognostic marker and a therapeutic target for drug resistance in colorectal cancer.