Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer.
Cancer Cell, 2023/02/13;41(2):252-271.e9.
Martinez-Ordoñez A[1], Duran A[1], Ruiz-Martinez M[1], Cid-Diaz T[1], Zhang X[1], Han Q[1], Kinoshita H[1], Muta Y[1], Linares JF[1], Kasashima H[2], Nakanishi Y[3], Omar M[1], Nishimura S[1], Avila L[1], Yashiro M[2], Maeda K[2], Pannellini T[1], Pigazzi A[4], Inghirami G[1], Marchionni L[1], Sigal D[5], Diaz-Meco MT[6], Moscat J[7]
Affiliations
PMID: 36525970DOI: 10.1016/j.ccell.2022.11.016
Impact factor: 38.585
Abstract
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.
Keywords: aPKC; colorectal cancer; hyaluronan; immune checkpoint therapy; immunosuppression; inflammation; liver metastasis; mesenchymal; stroma; tumor microenvironment
MeSH terms
Humans; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; Hyaluronic Acid; Immunotherapy; Sarcoma; Tumor Microenvironment
More resources
Full text:
Europe PubMed Central; PubMed Central
EndNote: Download