Glandular architecture and malignant behaviour in colorectal cancer is regulated by the sialomucin Podocalyxin.
Glandular architecture-the coordination of lumen-containing structures by an apical-basal polarised epithelium-is frequently maintained in colorectal cancer (CRC), yet whether it actively contributes to tumour progression or metastatic competence remains unclear. Here, we identify Podocalyxin (PODXL), a developmental regulator of epithelial lumen formation, as a key determinant of glandular tumour architecture in CRC. PODXL is upregulated in CRC, particularly in poor-prognosis Consensus Molecular Subtype 4 (CMS4) tumours, where high expression predicts reduced survival. Using genetically engineered mouse models, matched organoids, human cell lines and xenografts, we show that PODXL promotes organisation of CRC cells into gland-like, lumen-containing structures. Loss of PODXL disrupts glandular architecture in both primary tumours and liver metastases, reducing tumour growth and metastatic colonisation. Mechanistically, TGF-{beta} signalling drives PODXL upregulation. Together, these findings establish glandular architecture as an active determinant of CRC progression and identify PODXL as a functional contributor rather than merely a prognostic biomarker.