Multiomic spatial atlas shows deleted in malignant brain tumors 1 (DMBT1) glycoprotein is lost in colonic dysplasia
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| Format: | Artículo Open Access |
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Wiley
2025
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| author | Emily H Green Subhag R Kotrannavar Megan E Rutherford Hannah M Lunnemann Harsimran Kaur Cody N Heiser Hua Ding Alan J Simmons Xiao Liu D Borden Lacy M Kay Washington Martha J Shrubsole Qi Liu Ken S Lau Cynthia L Sears Robert J Coffey Julia L Drewes Nicholas O Markham |
| author_facet | Emily H Green Subhag R Kotrannavar Megan E Rutherford Hannah M Lunnemann Harsimran Kaur Cody N Heiser Hua Ding Alan J Simmons Xiao Liu D Borden Lacy M Kay Washington Martha J Shrubsole Qi Liu Ken S Lau Cynthia L Sears Robert J Coffey Julia L Drewes Nicholas O Markham Emily H Green Subhag R Kotrannavar Megan E Rutherford Hannah M Lunnemann Harsimran Kaur Cody N Heiser Hua Ding Alan J Simmons Xiao Liu D Borden Lacy M Kay Washington Martha J Shrubsole Qi Liu Ken S Lau Cynthia L Sears Robert J Coffey Julia L Drewes Nicholas O Markham |
| collection | Wiley Open Access |
| contents | Multiomic spatial atlas shows deleted in malignant brain tumors 1 (DMBT1) glycoprotein is lost in colonic dysplasia Emily H Green Subhag R Kotrannavar Megan E Rutherford Hannah M Lunnemann Harsimran Kaur Cody N Heiser Hua Ding Alan J Simmons Xiao Liu D Borden Lacy M Kay Washington Martha J Shrubsole Qi Liu Ken S Lau Cynthia L Sears Robert J Coffey Julia L Drewes Nicholas O Markham The Journal of Pathology AbstractColorectal cancer (CRC) is responsible for over 900,000 annual deaths worldwide. Emerging evidence supports pro‐carcinogenic bacteria in the colonic microbiome are at least promotional in CRC development and may be causal. We previously showed toxigenic C. difficile from human CRC‐associated bacterial biofilms accelerates tumorigenesis in ApcMin/+ mice, both in specific pathogen‐free mice and in gnotobiotic mice colonized with a defined consortium of bacteria. To further understand host–microbe interactions during colonic tumorigenesis, we combined single‐cell RNA‐sequencing (scRNA‐seq), spatial transcriptomics, and immunofluorescence to define the molecular spatial organization of colonic dysplasia in our consortium model with or without C. difficile. Our data show a striking bipartite regulation of Deleted in Malignant Brain Tumors 1 (DMBT1) in the inflamed versus dysplastic colon. From scRNA‐seq, differential gene expression analysis of normal absorptive colonocytes at 2 weeks postinoculation showed DMBT1 upregulated by C. difficile compared to colonocytes from mice without C. difficile exposure. In contrast, our spatial transcriptomic analysis showed DMBT1 dramatically downregulated in dysplastic foci compared with normal‐adjacent tissue. We further integrated our datasets to generate custom colonic dysplasia scores and ligand‐receptor mapping. Validation with immunofluorescence showed DMBT1 protein downregulated in dysplastic foci from three mouse models of colonic tumorigenesis and in adenomatous dysplasia from human samples. Finally, we used mouse and human organoids to implicate WNT signaling in the downregulation of DMBT1 mRNA and protein. Together, our data reveal cell type‐specific regulation of DMBT1, a potential mechanistic link between bacteria and colonic tumorigenesis. Published 2025. This article is a U.S. Government work and is in the public domain in the USA. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. 10.1002/path.6406 http://creativecommons.org/licenses/by-nc/4.0/ |
| doi_str_mv | 10.1002/path.6406 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_path_6406 |
| institution | Wiley Open Access |
| license_str_mv | http://creativecommons.org/licenses/by-nc/4.0/ |
| publishDate | 2025 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Multiomic spatial atlas shows deleted in malignant brain tumors 1 (DMBT1) glycoprotein is lost in colonic dysplasia Emily H Green Subhag R Kotrannavar Megan E Rutherford Hannah M Lunnemann Harsimran Kaur Cody N Heiser Hua Ding Alan J Simmons Xiao Liu D Borden Lacy M Kay Washington Martha J Shrubsole Qi Liu Ken S Lau Cynthia L Sears Robert J Coffey Julia L Drewes Nicholas O Markham The Journal of Pathology Multiomic spatial atlas shows deleted in malignant brain tumors 1 (DMBT1) glycoprotein is lost in colonic dysplasia Emily H Green Subhag R Kotrannavar Megan E Rutherford Hannah M Lunnemann Harsimran Kaur Cody N Heiser Hua Ding Alan J Simmons Xiao Liu D Borden Lacy M Kay Washington Martha J Shrubsole Qi Liu Ken S Lau Cynthia L Sears Robert J Coffey Julia L Drewes Nicholas O Markham The Journal of Pathology AbstractColorectal cancer (CRC) is responsible for over 900,000 annual deaths worldwide. Emerging evidence supports pro‐carcinogenic bacteria in the colonic microbiome are at least promotional in CRC development and may be causal. We previously showed toxigenic C. difficile from human CRC‐associated bacterial biofilms accelerates tumorigenesis in ApcMin/+ mice, both in specific pathogen‐free mice and in gnotobiotic mice colonized with a defined consortium of bacteria. To further understand host–microbe interactions during colonic tumorigenesis, we combined single‐cell RNA‐sequencing (scRNA‐seq), spatial transcriptomics, and immunofluorescence to define the molecular spatial organization of colonic dysplasia in our consortium model with or without C. difficile. Our data show a striking bipartite regulation of Deleted in Malignant Brain Tumors 1 (DMBT1) in the inflamed versus dysplastic colon. From scRNA‐seq, differential gene expression analysis of normal absorptive colonocytes at 2 weeks postinoculation showed DMBT1 upregulated by C. difficile compared to colonocytes from mice without C. difficile exposure. In contrast, our spatial transcriptomic analysis showed DMBT1 dramatically downregulated in dysplastic foci compared with normal‐adjacent tissue. We further integrated our datasets to generate custom colonic dysplasia scores and ligand‐receptor mapping. Validation with immunofluorescence showed DMBT1 protein downregulated in dysplastic foci from three mouse models of colonic tumorigenesis and in adenomatous dysplasia from human samples. Finally, we used mouse and human organoids to implicate WNT signaling in the downregulation of DMBT1 mRNA and protein. Together, our data reveal cell type‐specific regulation of DMBT1, a potential mechanistic link between bacteria and colonic tumorigenesis. Published 2025. This article is a U.S. Government work and is in the public domain in the USA. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. 10.1002/path.6406 http://creativecommons.org/licenses/by-nc/4.0/ |
| title | Multiomic spatial atlas shows deleted in malignant brain tumors 1 (DMBT1) glycoprotein is lost in colonic dysplasia |
| topic | The Journal of Pathology |
| url | https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6406 |