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

TitleHyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer.
Publication TypeJournal Article
Year of Publication2023
AuthorsMartinez-Ordoñez A, Duran A, Ruiz-Martinez M, Cid-Diaz T, Zhang X, Han Q, Kinoshita H, Muta Y, Linares JF, Kasashima H, Nakanishi Y, Omar M, Nishimura S, Avila L, Yashiro M, Maeda K, Pannellini T, Pigazzi A, Inghirami G, Marchionni L, Sigal D, Diaz-Meco MT, Moscat J
JournalCancer Cell
Volume41
Issue2
Pagination252-271.e9
Date Published2023 Feb 13
ISSN1878-3686
KeywordsCD8-Positive T-Lymphocytes, Colorectal Neoplasms, Humans, Hyaluronic Acid, Immunotherapy, Sarcoma, Tumor Microenvironment
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.

DOI10.1016/j.ccell.2022.11.016
Alternate JournalCancer Cell
PubMed ID36525970
PubMed Central IDPMC9931663
Grant ListR01 CA246765 / CA / NCI NIH HHS / United States
R01 CA250025 / CA / NCI NIH HHS / United States
R01 CA265892 / CA / NCI NIH HHS / United States
R50 CA265332 / CA / NCI NIH HHS / United States
Related Faculty: 
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D. Luigi Marchionni, M.D., Ph.D. Giorgio Inghirami, M.D. Maria Angeles Duran, Ph.D. Juan Francisco Linares Rodriguez, Ph.D. Mohamed Omar, MB, BCh

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