PLCγ1 in curdione-mediated angiogenesis-EMT interaction and colorectal cancer metastasis.

[BACKGROUND] In colorectal cancer (CRC), aberrant tumor vasculature and epithelial-mesenchymal transition (EMT) synergistically drive distant metastasis, profoundly influencing patient prognosis. However, the underlying molecular mechanism and effective systemic therapeutic strategies remain unclear.

[PURPOSE] This study aimed to identify key molecular drivers of the vascular anomaly-EMT-metastasis axis in CRC and to evaluate the therapeutic potential of Curdione, a bioactive natural compound, in disrupting this pathological loop.

[STUDY DESIGN] We employed integrated in vitro and in vivo experimental systems, supported by multi-omics and single-cell analyses, to investigate the role of phospholipase C gamma 1 (PLCγ1) in CRC progression and its modulation by Curdione.

[METHODS] CRC patient-derived organoid and animal metastasis models were established, and functional assays were conducted to assess tumor invasiveness, vascular integrity, and EMT phenotype. Multi-omics profiling and mechanistic studies identified molecular targets and signaling pathways. Combination therapy with Curdione and Bevacizumab was further evaluated to determine synergistic effects.

[RESULTS] Multi-omics analyses identified PLCγ1 as a central target of Curdione. Mechanistic analyses suggest that PLCγ1 is involved in the regulation of vascular abnormality, endothelial barrier dysfunction, and EMT, at least in part through the PKC-PI3K signaling pathway, which is associated with features of a prometastatic microenvironment. Curdione treatment was associated with enhanced PLCγ1 degradation and attenuation of downstream signaling, accompanied by improved vascular integrity, reinforced epithelial stability, and a reduction in metastatic phenotypes Moreover, combined treatment with Curdione and Bevacizumab was associated with enhanced anti-angiogenic effects and reduced EMT-associated features.

[CONCLUSION] This study identifies the PLCγ1-PKC-PI3K signaling axis as a key pathway associated with the coordination of vascular abnormality, EMT, and metastatic phenotypes in CRC. Our findings suggest that Curdione functions as a natural multi-target modulator of the tumor microenvironment and, when combined with Bevacizumab, may enhance anti-metastatic efficacy in CRC models.