Signaling downstream of tumor-stroma interaction regulates mucinous colorectal adenocarcinoma apicobasal polarity

: Mucinous colorectal carcinoma (MUC CRC) metastasis to multiple organs, and to the peritoneum, is associated with poor prognosis. Disseminating MUC CRCs exhibit either conventional (apical-in) or inverted (apical-out) polarity that influence patient outcomes. Therefore, it is critical to identify how MUC CRC polarity is regulated. Here, we analyze patient-derived MUC CRC xenografts with either apical-in or apical-out polarity. Single-cell analyses reveal α2β1-integrin as a key collagen-binding receptor in these models. Collagen-α2β1-integrin interaction activates Src and upregulates SorLA, an endosomal sorting receptor. SorLA supports apical-in polarity by promoting integrin recycling and HER2/HER3 expression. We observe positive correlation between HER2, HER3 and SorLA in patient samples and higher HER2 expression in apical-in-presenting tissues. Clinically relevant HER2/HER3-targeting antibodies revert tumor sphere polarity, and impede collagen remodeling and adhesion to mouse peritoneum. This SorLA-integrin-HER2/HER3 axis could represent a MUC CRC-patient stratification approach and be relevant for other carcinomas with apical-out phenotypes.