Transcriptomic and immunophenotypic profiling reveals molecular and immunological hallmarks of colorectal cancer tumourigenesis

ObjectiveBiological insights into the stepwise development and progression of colorectal cancer (CRC) are imperative to develop tailored approaches for early detection and optimal clinical management of this disease. Here, we aimed to dissect the transcriptional and immunologic alterations that acco...

Full description

Saved in:
Bibliographic Details
Published in:Gut Vol. 72; no. 7; pp. 1326 - 1339
Main Authors: Roelands, Jessica, van der Ploeg, Manon, Ijsselsteijn, Marieke E, Dang, Hao, Boonstra, Jurjen J, Hardwick, James C H, Hawinkels, Lukas J A C, Morreau, Hans, de Miranda, Noel F C C
Format: Journal Article
Language:English
Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.07.2023
BMJ Publishing Group LTD
BMJ Publishing Group
Series:Original research
Subjects:
Biomarkers
Cancer
Cell Transformation, Neoplastic - genetics
Colon
Colorectal cancer
Colorectal carcinoma
colorectal neogenesis
Colorectal Neoplasms - pathology
Cytometry
Dysplasia
Endoscopy
Epithelium
Gene expression
Gene Expression Profiling
Genetic transformation
Genomics
Histocompatibility antigen HLA
Humans
immunogenetics
Inflammation
Macrophages
Metastases
Myeloid cells
Patients
Transcriptome
Transcriptomics
Tumorigenesis
Tumors
colorectal neogenesis
immunogenetics
gene expression
ISSN:0017-5749, 1468-3288, 1468-3288
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:ObjectiveBiological insights into the stepwise development and progression of colorectal cancer (CRC) are imperative to develop tailored approaches for early detection and optimal clinical management of this disease. Here, we aimed to dissect the transcriptional and immunologic alterations that accompany malignant transformation in CRC and to identify clinically relevant biomarkers through spatial profiling of pT1 CRC samples.DesignWe employed digital spatial profiling (GeoMx) on eight pT1 CRCs to study gene expression in the epithelial and stromal segments across regions of distinct histology, including normal mucosa, low-grade and high-grade dysplasia and cancer. Consecutive histology sections were profiled by imaging mass cytometry to reveal immune contextures. Finally, publicly available single-cell RNA-sequencing data was analysed to determine the cellular origin of relevant transcripts.ResultsComparison of gene expression between regions within pT1 CRC samples identified differentially expressed genes in the epithelium (n=1394 genes) and the stromal segments (n=1145 genes) across distinct histologies. Pathway analysis identified an early onset of inflammatory responses during malignant transformation, typified by upregulation of gene signatures such as innate immune sensing. We detected increased infiltration of myeloid cells and a shift in macrophage populations from pro-inflammatory HLA-DR+CD204− macrophages to HLA-DR−CD204+ immune-suppressive subsets from normal tissue through dysplasia to cancer, accompanied by the upregulation of the CD47/SIRPα ‘don’t eat me signal’.ConclusionSpatial profiling revealed the molecular and immunological landscape of CRC tumourigenesis at early disease stage. We identified biomarkers with strong association with disease progression as well as targetable immune processes that are exploitable in a clinical setting.
Bibliography:Original research
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:0017-5749
1468-3288
1468-3288
DOI:10.1136/gutjnl-2022-327608