Mechanobiological Ultrasound Simulation Reveals Suppression of Epithelial-to-Mesenchymal Transition and Stemness Programs in Colorectal Cancer.

[BACKGROUND] Dynamic characteristics such as cancer stemness and the epithelial-to-mesenchymal transition (EMT) cause the spread of colorectal cancer (CRC). Although there are now few pharmaceutical approaches, therapeutically correcting these conditions may improve prognosis. Acoustic radiation force and other mechanical ultrasonic forces have become new, noninvasive methods for modifying tumor biology. Nevertheless, little is known about their molecular influence on CRC EMT-stemness pathways.

[MATERIALS AND METHODS] The authors created a simulation pipeline to predict the effects of ultrasound-induced mechanical stress on CRC samples enriched for tumor-infiltrating T cells using transcriptome datasets (GSE108989). Heatmap visualizations, differential expression, pathway enrichment, principal component analysis (PCA), and EMT and stemness scores were computed using bulk RNA-seq. To evaluate mechanistic suppression, signaling axes such as TGF-β, Wnt/β-catenin, Notch, and yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) were investigated. The potential ultrasonic sensitivity of key gene modules was assessed.

[RESULTS] Mesenchymal and stemness-associated transcriptional pathways were found to be downregulated in response to simulated acoustic modulation. Coherent clustering of decreased EMT/stemness genes was shown via heatmaps. Modified tumor groupings were identified by PCA. In the simulated postultrasound condition, canonical pathways associated with invasion, immunological evasion, and stemness maintenance were diminished. These results lend credence to the theory that CRC cellular plasticity may be reprogrammed by mechanical ultrasonic force.

[CONCLUSIONS] Early mechanistic understanding of how acoustic force-based ultrasound may inhibit EMT and stemness in CRC is provided by this transcriptome simulation. This data-driven approach presents ultrasound as a promising supplement to immune-oncology and antimetastatic methods and encourages more validation.