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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE207782 | GEO | 2022/12/16

REPOSITORIES: GEO

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

Project description: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.

2022-12-16 | GSE207778 | GEO

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

2022-12-16 | GSE207776 | GEO

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

2022-12-16 | GSE207780 | GEO

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

2022-12-16 | GSE207779 | GEO

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

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

| PRJNA857052 | ENA

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

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

| PRJNA857057 | ENA

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

Project description:Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a therapeutic vulnerability in mesenchymal colorectal cancer I

| PRJNA857058 | ENA

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

Project description:Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a therapeutic vulnerability in mesenchymal colorectal cancer III

| PRJNA857056 | ENA

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

Project description:Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a therapeutic vulnerability in mesenchymal colorectal cancer IV

| PRJNA857055 | ENA

TP53 loss creates therapeutic vulnerability in colorectal cancer.

Project description:TP53, a well-known tumour suppressor gene that encodes p53, is frequently inactivated by mutation or deletion in most human tumours. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment owing to the complexity of p53 signalling. Here we demonstrate that genomic deletion of TP53 frequently encompasses essential neighbouring genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene that is almost always co-deleted with TP53 in human cancers. It encodes the largest and catalytic subunit of the RNA polymerase II complex, which is specifically inhibited by α-amanitin. Our analysis of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal cancer. Suppression of POLR2A with α-amanitin or small interfering RNAs selectively inhibits the proliferation, survival and tumorigenic potential of colorectal cancer cells with hemizygous TP53 loss in a p53-independent manner. Previous clinical applications of α-amanitin have been limited owing to its liver toxicity. However, we found that α-amanitin-based antibody-drug conjugates are highly effective therapeutic agents with reduced toxicity. Here we show that low doses of α-amanitin-conjugated anti-epithelial cell adhesion molecule (EpCAM) antibody lead to complete tumour regression in mouse models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a new therapeutic approach for human cancers containing such common genomic alterations.

| S-EPMC4417759 | biostudies-literature

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