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...

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Veröffentlicht in:	Gut Jg. 72; H. 7; S. 1326 - 1339
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.07.2023 BMJ Publishing Group LTD BMJ Publishing Group
Schriftenreihe:	Original research
Schlagworte:	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
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Abstract	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.
AbstractList	Biological 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. We 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. Comparison 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'. Spatial 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. 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. Biological 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.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.We 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.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.Comparison 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'.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'.Spatial 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.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.
Author	Ijsselsteijn, Marieke E van der Ploeg, Manon Dang, Hao Hawinkels, Lukas J A C Hardwick, James C H Morreau, Hans Roelands, Jessica de Miranda, Noel F C C Boonstra, Jurjen J
AuthorAffiliation	1 Department of Pathology , Leiden University Medical Center , Leiden , The Netherlands 2 Department of Gastroenterology and Hepatology , Leiden University Medical Center , Leiden , The Netherlands
AuthorAffiliation_xml	– name: 1 Department of Pathology , Leiden University Medical Center , Leiden , The Netherlands – name: 2 Department of Gastroenterology and Hepatology , Leiden University Medical Center , Leiden , The Netherlands
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Keywords	colorectal neogenesis immunogenetics gene expression
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PublicationDate	2023-07-01
PublicationDateYYYYMMDD	2023-07-01
PublicationDate_xml	– month: 07 year: 2023 text: 2023-07-01 day: 01
PublicationDecade	2020
PublicationPlace	England
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PublicationYear	2023
Publisher	BMJ Publishing Group Ltd and British Society of Gastroenterology BMJ Publishing Group LTD BMJ Publishing Group
Publisher_xml	– name: BMJ Publishing Group Ltd and British Society of Gastroenterology – name: BMJ Publishing Group LTD – name: BMJ Publishing Group
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Snippet	ObjectiveBiological insights into the stepwise development and progression of colorectal cancer (CRC) are imperative to develop tailored approaches for early... Biological insights into the stepwise development and progression of colorectal cancer (CRC) are imperative to develop tailored approaches for early detection...
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SubjectTerms	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
Title	Transcriptomic and immunophenotypic profiling reveals molecular and immunological hallmarks of colorectal cancer tumourigenesis
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