Patient-derived organoids identify an apico-basolateral polarity switch associated with survival in colorectal cancer

The metastatic progression of cancer remains a major issue in patient treatment. Yet, the molecular and cellular mechanisms underlying this process remains unclear. Here, we use primary explants and organoids from patients harboring mucinous colorectal carcinoma (MUC CRC), a poor prognosis histological form of digestive cancers, to study the architecture, invasive behavior and chemoresistance of tumor cell intermediates. We report that these tumors maintain a robust apico-basolateral polarity as they spread in the peritumoral stroma or organotypic collagen-I gels. We identified two distinct topologies: MUC CRCs either display a conventional "apical-in" polarity or, more frequently, harbor an inverted "apical-out" topology. Transcriptomic analyses combined with interference experiments on organoids showed that TGFb and focal adhesion signaling pathways are the main drivers of polarity orientation. Finally, this apical-out topology is associated with increased resistance to chemotherapeutic treatments in organoids and decreased patient survival in the clinic. Thus, patient-derived organoids have the potential to bridge histological, cellular and molecular analyses to decrypt onco-morphogenic programs and stratify cancer patients.