Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a therapeutic vulnerability in mesenchymal colorectal cancer II

Mesenchymal colorectal cancer (mCRC) is microsatellite stable (MSS), highly desmoplastic, with CD8+ T cells excluded to the stromal periphery, resistant to immunotherapy, and is driven by low levels of the atypical PKCs (aPKCs). We show here that a salient feature of these tumors is the accumulation of hyaluronan (HA), which along with reduced aPKC levels, predict poor survival. HA promotes epithelial heterogeneity, and the emergence of a fetal metaplastic cell population (TFSC) endowed with invasive cancer features through a network of interactions with activated fibroblasts and components of the immune system. TFSCs are sensitive to HA deposition in vivo and organoids, and their gene expression signature has prognostic value. We demonstrate that in vivo HA degradation with a clinical dose of hyaluronidase impairs mCRC tumorigenesis and enables immune checkpoint blockade therapy by promoting the recruitment of B and CD8+ T cells, including a proportion with resident memory features. Overall design: Prkcif/fPrkczf/f;Villin-Cre Veh- (n=3) and PEGPH20-treated (n=3) small intestine tumors were profiled