The Transcriptomic Landscape of Mismatch Repair-Deficient Intestinal Stem Cells
Lynch syndrome is the most common cause of hereditary colorectal cancer and is secondary to germline alterations in one of four DNA mismatch repair (MMR) genes. Here we aimed to provide novel insights into the initiation of MMR-deficient (MMRd) colorectal carcinogenesis by characterizing the express...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Jg. 81; H. 10; S. 2760 |
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15.05.2021
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| Abstract | Lynch syndrome is the most common cause of hereditary colorectal cancer and is secondary to germline alterations in one of four DNA mismatch repair (MMR) genes. Here we aimed to provide novel insights into the initiation of MMR-deficient (MMRd) colorectal carcinogenesis by characterizing the expression profile of MMRd intestinal stem cells (ISC). A tissue-specific MMRd mouse model (Villin-Cre;Msh2
) was crossed with a reporter mouse (
) to trace and isolate ISCs (Lgr5+) using flow cytometry. Three different ISC genotypes (
-KO,
-HET, and
-WT) were isolated and processed for mRNA-seq and mass spectrometry, followed by bioinformatic analyses to identify expression signatures of complete MMRd and haplo-insufficiency. These findings were validated using qRT-PCR, IHC, and whole transcriptomic sequencing in mouse tissues, organoids, and a cohort of human samples, including normal colorectal mucosa, premalignant lesions, and early-stage colorectal cancers from patients with Lynch syndrome and patients with familial adenomatous polyposis (FAP) as controls.
-KO ISCs clustered together with differentiated intestinal epithelial cells from all genotypes. Gene-set enrichment analysis indicated inhibition of replication, cell-cycle progression, and the Wnt pathway and activation of epithelial signaling and immune reaction. An expression signature derived from MMRd ISCs successfully distinguished MMRd neoplastic lesions of patients with Lynch syndrome from FAP controls. SPP1 was specifically upregulated in MMRd ISCs and colocalized with LGR5 in Lynch syndrome colorectal premalignant lesions and tumors. These results show that expression signatures of MMRd ISC recapitulate the initial steps of Lynch syndrome carcinogenesis and have the potential to unveil novel biomarkers of early cancer initiation. SIGNIFICANCE: The transcriptomic and proteomic profile of MMR-deficient intestinal stem cells displays a unique set of genes with potential roles as biomarkers of cancer initiation and early progression. |
|---|---|
| AbstractList | Lynch syndrome is the most common cause of hereditary colorectal cancer and is secondary to germline alterations in one of four DNA mismatch repair (MMR) genes. Here we aimed to provide novel insights into the initiation of MMR-deficient (MMRd) colorectal carcinogenesis by characterizing the expression profile of MMRd intestinal stem cells (ISC). A tissue-specific MMRd mouse model (Villin-Cre;Msh2
) was crossed with a reporter mouse (
) to trace and isolate ISCs (Lgr5+) using flow cytometry. Three different ISC genotypes (
-KO,
-HET, and
-WT) were isolated and processed for mRNA-seq and mass spectrometry, followed by bioinformatic analyses to identify expression signatures of complete MMRd and haplo-insufficiency. These findings were validated using qRT-PCR, IHC, and whole transcriptomic sequencing in mouse tissues, organoids, and a cohort of human samples, including normal colorectal mucosa, premalignant lesions, and early-stage colorectal cancers from patients with Lynch syndrome and patients with familial adenomatous polyposis (FAP) as controls.
-KO ISCs clustered together with differentiated intestinal epithelial cells from all genotypes. Gene-set enrichment analysis indicated inhibition of replication, cell-cycle progression, and the Wnt pathway and activation of epithelial signaling and immune reaction. An expression signature derived from MMRd ISCs successfully distinguished MMRd neoplastic lesions of patients with Lynch syndrome from FAP controls. SPP1 was specifically upregulated in MMRd ISCs and colocalized with LGR5 in Lynch syndrome colorectal premalignant lesions and tumors. These results show that expression signatures of MMRd ISC recapitulate the initial steps of Lynch syndrome carcinogenesis and have the potential to unveil novel biomarkers of early cancer initiation. SIGNIFICANCE: The transcriptomic and proteomic profile of MMR-deficient intestinal stem cells displays a unique set of genes with potential roles as biomarkers of cancer initiation and early progression. Lynch syndrome is the most common cause of hereditary colorectal cancer and is secondary to germline alterations in one of four DNA mismatch repair (MMR) genes. Here we aimed to provide novel insights into the initiation of MMR-deficient (MMRd) colorectal carcinogenesis by characterizing the expression profile of MMRd intestinal stem cells (ISC). A tissue-specific MMRd mouse model (Villin-Cre;Msh2 LoxP/LoxP ) was crossed with a reporter mouse (Lgr5-EGFP-IRES-creERT2) to trace and isolate ISCs (Lgr5+) using flow cytometry. Three different ISC genotypes (Msh2-KO, Msh2-HET, and Msh2-WT) were isolated and processed for mRNA-seq and mass spectrometry, followed by bioinformatic analyses to identify expression signatures of complete MMRd and haplo-insufficiency. These findings were validated using qRT-PCR, IHC, and whole transcriptomic sequencing in mouse tissues, organoids, and a cohort of human samples, including normal colorectal mucosa, premalignant lesions, and early-stage colorectal cancers from patients with Lynch syndrome and patients with familial adenomatous polyposis (FAP) as controls. Msh2-KO ISCs clustered together with differentiated intestinal epithelial cells from all genotypes. Gene-set enrichment analysis indicated inhibition of replication, cell-cycle progression, and the Wnt pathway and activation of epithelial signaling and immune reaction. An expression signature derived from MMRd ISCs successfully distinguished MMRd neoplastic lesions of patients with Lynch syndrome from FAP controls. SPP1 was specifically upregulated in MMRd ISCs and colocalized with LGR5 in Lynch syndrome colorectal premalignant lesions and tumors. These results show that expression signatures of MMRd ISC recapitulate the initial steps of Lynch syndrome carcinogenesis and have the potential to unveil novel biomarkers of early cancer initiation. SIGNIFICANCE: The transcriptomic and proteomic profile of MMR-deficient intestinal stem cells displays a unique set of genes with potential roles as biomarkers of cancer initiation and early progression.Lynch syndrome is the most common cause of hereditary colorectal cancer and is secondary to germline alterations in one of four DNA mismatch repair (MMR) genes. Here we aimed to provide novel insights into the initiation of MMR-deficient (MMRd) colorectal carcinogenesis by characterizing the expression profile of MMRd intestinal stem cells (ISC). A tissue-specific MMRd mouse model (Villin-Cre;Msh2 LoxP/LoxP ) was crossed with a reporter mouse (Lgr5-EGFP-IRES-creERT2) to trace and isolate ISCs (Lgr5+) using flow cytometry. Three different ISC genotypes (Msh2-KO, Msh2-HET, and Msh2-WT) were isolated and processed for mRNA-seq and mass spectrometry, followed by bioinformatic analyses to identify expression signatures of complete MMRd and haplo-insufficiency. These findings were validated using qRT-PCR, IHC, and whole transcriptomic sequencing in mouse tissues, organoids, and a cohort of human samples, including normal colorectal mucosa, premalignant lesions, and early-stage colorectal cancers from patients with Lynch syndrome and patients with familial adenomatous polyposis (FAP) as controls. Msh2-KO ISCs clustered together with differentiated intestinal epithelial cells from all genotypes. Gene-set enrichment analysis indicated inhibition of replication, cell-cycle progression, and the Wnt pathway and activation of epithelial signaling and immune reaction. An expression signature derived from MMRd ISCs successfully distinguished MMRd neoplastic lesions of patients with Lynch syndrome from FAP controls. SPP1 was specifically upregulated in MMRd ISCs and colocalized with LGR5 in Lynch syndrome colorectal premalignant lesions and tumors. These results show that expression signatures of MMRd ISC recapitulate the initial steps of Lynch syndrome carcinogenesis and have the potential to unveil novel biomarkers of early cancer initiation. SIGNIFICANCE: The transcriptomic and proteomic profile of MMR-deficient intestinal stem cells displays a unique set of genes with potential roles as biomarkers of cancer initiation and early progression. |
| Author | Wu, Wenhui Ozcan, Zuhal Katayama, Hiroyuki Rocha, Pedro Francisco-Cruz, Alejandro Tosti, Elena Wu, Hong Taggart, Melissa W Bowen, Charles M Edelmann, Winfried Hanash, Samir M Vilar, Eduardo Reyes-Uribe, Laura Wistuba, Ignacio I Bommi, Prashant V Sinha, Krishna M Burks, Jared K Scheet, Paul A Willis, Jason A Lynch, Patrick M Parra, Edwin R |
| Author_xml | – sequence: 1 givenname: Prashant V orcidid: 0000-0002-9457-1730 surname: Bommi fullname: Bommi, Prashant V organization: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 2 givenname: Charles M orcidid: 0000-0001-5400-4304 surname: Bowen fullname: Bowen, Charles M organization: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 3 givenname: Laura surname: Reyes-Uribe fullname: Reyes-Uribe, Laura organization: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 4 givenname: Wenhui surname: Wu fullname: Wu, Wenhui organization: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 5 givenname: Hiroyuki orcidid: 0000-0003-3117-1390 surname: Katayama fullname: Katayama, Hiroyuki organization: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 6 givenname: Pedro surname: Rocha fullname: Rocha, Pedro organization: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 7 givenname: Edwin R orcidid: 0000-0001-9068-1636 surname: Parra fullname: Parra, Edwin R organization: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 8 givenname: Alejandro orcidid: 0000-0002-1558-8084 surname: Francisco-Cruz fullname: Francisco-Cruz, Alejandro organization: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 9 givenname: Zuhal orcidid: 0000-0002-8693-1935 surname: Ozcan fullname: Ozcan, Zuhal organization: Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 10 givenname: Elena surname: Tosti fullname: Tosti, Elena organization: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York – sequence: 11 givenname: Jason A orcidid: 0000-0001-8238-8552 surname: Willis fullname: Willis, Jason A organization: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 12 givenname: Hong surname: Wu fullname: Wu, Hong organization: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 13 givenname: Melissa W orcidid: 0000-0002-7803-9904 surname: Taggart fullname: Taggart, Melissa W organization: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 14 givenname: Jared K orcidid: 0000-0002-6173-9074 surname: Burks fullname: Burks, Jared K organization: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 15 givenname: Patrick M surname: Lynch fullname: Lynch, Patrick M organization: Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 16 givenname: Winfried surname: Edelmann fullname: Edelmann, Winfried organization: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York – sequence: 17 givenname: Paul A surname: Scheet fullname: Scheet, Paul A organization: Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 18 givenname: Ignacio I surname: Wistuba fullname: Wistuba, Ignacio I organization: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 19 givenname: Krishna M surname: Sinha fullname: Sinha, Krishna M organization: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 20 givenname: Samir M surname: Hanash fullname: Hanash, Samir M organization: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 21 givenname: Eduardo orcidid: 0000-0001-6404-3761 surname: Vilar fullname: Vilar, Eduardo email: EVilar@mdanderson.org organization: Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas |
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| SubjectTerms | Animals Apoptosis Carcinogenesis - genetics Carcinogenesis - metabolism Carcinogenesis - pathology Cell Proliferation Colorectal Neoplasms, Hereditary Nonpolyposis - genetics Colorectal Neoplasms, Hereditary Nonpolyposis - metabolism Colorectal Neoplasms, Hereditary Nonpolyposis - pathology DNA Mismatch Repair Gene Expression Regulation, Neoplastic Humans Intestines - physiopathology Mice Mice, Inbred C57BL Mice, Knockout MutS Homolog 2 Protein - physiology Prognosis Proteome - analysis Proteome - metabolism Receptors, G-Protein-Coupled - physiology Stem Cells - metabolism Stem Cells - pathology Survival Rate Transcriptome Tumor Cells, Cultured |
| Title | The Transcriptomic Landscape of Mismatch Repair-Deficient Intestinal Stem Cells |
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