Proteolytic processing converts pro-tumorigenic Angiopoietin-like 4 into an inhibitor of metastasis

Preclinical and clinical studies have solidly established the concepts of concomitant tumor resistance (CTR), the inhibition of metastases formation by the primary tumor. Yet, the mechanisms of CTR are poorly understood and bench-to-bedside studies are largely missing. Here, we show that proteolytic processing of ANGPTL4 liberated the potent CTR-inducing capacity of the N-terminal cleavage fragment, nANGPTL4. Full-length ANGPTL4 was primarily detected in tumor tissues, whereas nANGPTL4 predominated in the systemic circulation, whose concentrations correlated inversely with disease progression. Comparative studies in multiple preclinical tumor models revealed distinctly opposing functions of the ANGPTL4 cleavage fragments. Full length and cANGPTL4 promoted tumor growth and metastasis leading to reduced overall survival. Conversely, nANGPTL4 inhibited metastasis formation and enhanced overall survival. The experiments identified proteolytic cleavage as regulatory mechanism converting pro-tumorigenic ANGPTL4 into anti-metastatic nANGPTL4. Moreover, the results revitalize the concept that primary tumors may suppress metastases through systemic release of metastasis-inhibiting cytokines