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

Overview

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.

publication date

  • December 15, 2022

Research

keywords

  • Colorectal Neoplasms
  • Hyaluronic Acid
  • Tumor Microenvironment

Identity

PubMed Central ID

  • PMC9931663

Scopus Document Identifier

  • 85147579023

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2019.05.031

PubMed ID

  • 36525970

Additional Document Info

volume

  • 41

issue

  • 2