Retromer complex: A novel regulator of melanoma metastasis

The VPS35/Retromer complex plays a crucial role in regulating MT1-MMP, an enzyme essential for cancer metastasis, by controlling both its stability and recycling. The complex binds to MT1-MMP, preventing its breakdown in lysosomes and facilitating its recycle to the cell membrane. VPS35 depletion reduces MT1-MMP protein stability, increases lysosomal degradation, and reduces MT1-MMP levels both on the cell membrane and within the cell. In models of lung metastasis, melanoma cells lacking VPS35 exhibited significantly reduced metastasis. Importantly, restoring MT1-MMP levels rescued metastatic potential to control levels.

Further investigation revealed that the VPS35/Retromer complex also enhances MT1-MMP transcription through STAT3 signaling. Mechanistic studies revealed that VPS35/Retromer acts as a platform to facilitate STAT3 activation by IL-6, which then moves into the nucleus and enhances MT1-MMP transcription. When VPS35 is reduced, STAT3 activation is impaired, leading to decreased MT1-MMP mRNA levels. Clinical data from melanoma patients shows a strong positive correlation between VPS35 and MT1-MMP expression, with higher levels of both proteins associated with poorer prognosis.

This dual regulatory mechanism explains how targeting VPS35 disrupts both the "existing pool" and "new synthesis" of MT1-MMP, providing a solid theoretical basis for developing new therapies that target VPS35 to combat cancer metastasis.