Spatial regulation of the glycocalyx component Podocalyxin is a switch for pro-metastatic function

The glycocalyx component and sialomucin Podocalyxin (PODXL) is required for normal tissue development by promoting an apical membrane to form between adjacent cells, triggering lumen formation. Yet, elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumour types. How PODXL presents this duality in effect on tissue function remains unknown. We identify an unexpected function of PODXL as a decoy receptor for the extracellular glycocalyx component Galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by PODXL ubiquitination, is the molecular mechanism that controls whether PODXL can drive such alternate fates. Notably both states,PODXL high surface versus low surface levels, occur in parallel subpopulations within cancer cell lines. Orthotopic intraprostatic xenograft of PODXL-manipulated cells or those with different surface levels of PODXL define that this axis controls metastasis in vivo. Clinically, the interplay between PODXL-GAL3 stratifies prostate cancer patients with poor outcome. Our studies define the molecular mechanisms and context in which the glycocalyx component PODXL promotes invasion and metastasis.