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

Mesenchymal colorectal cancer (mCRC) is microsatellite stable (MSS), highly desmoplastic, with CD8+ T cells excluded to the stromal periphery, resistant to immunotherapy, and driven by low levels of the atypical protein kinase Cs (aPKCs) in the intestinal epithelium. We show here that a salient feature of these tumors is the accumulation of hyaluronan (HA) which, along with reduced aPKC levels, predicts poor survival. HA promotes epithelial heterogeneity and the emergence of a tumor fetal metaplastic cell (TFMC) population endowed with invasive cancer features through a network of interactions with activated fibroblasts. TFMCs are sensitive to HA deposition, and their metaplastic markers have prognostic value. We demonstrate that in vivo HA degradation with a clinical dose of hyaluronidase impairs mCRC tumorigenesis and liver metastasis and enables immune checkpoint blockade therapy by promoting the recruitment of B and CD8+ T cells, including a proportion with resident memory features, and by blocking immunosuppression. [Display omitted] • Reduced aPKC drives HA deposition, the mCRC phenotype, and predicts poor survival • HA enhances malignancy and promotes CAF and epithelial heterogeneity in mCRC • Immunosuppression is maintained by cross-compartment interactions driven by HA • HA depletion blocks mCRC tumorigenesis and liver metastasis enabling immunotherapy Mesenchymal colorectal cancer (mCRC) is a highly desmoplastic and immune-excluded tumor with a poor prognosis. Martinez-Ordoñez et al. demonstrate that the synthesis of hyaluronan driven by a deficiency in the atypical protein kinase Cs in epithelial cells is a critical event in mCRC by promoting stroma crosstalks with invasive fetal metaplastic cells and immunosuppression. [ABSTRACT FROM AUTHOR]