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.