Abstract 6693: Deleted in malignant brain tumors 1 (DMBT1) glycoprotein is lost in colonic dysplasia
Authors: Emily H. Green, Subhag R. Kotrannavar, Megan E. Rutherford, Harsimran Kaur, Hannah M. Lunnemann, Cody N. Heiser, Shaoguang Wu, Hua Ding, J. Alan Simmons, Xiao Liu, D. Borden Lacy, Martha J. Shrubsole, Qi Liu, Ken S. Lau, Cynthia L. Sears, Robert J. Coffey, Julia L. Drewes, Nicholas O. Markham
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is the third most common cancer in the United States and is responsible for more than 50,000 deaths annually. Emerging evidence strongly supports a causal role for specific pro-carcinogenic driver bacteria within the colonic microbiota. Invasive bacterial biofilms may initiate or accelerate CRC through epithelium-autonomous or inflammation-dependent mechanisms. To better 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 tissue from germ-free ApcMin/+ mice colonized with bacteria from human biofilm-associated CRC. In absorptive colonocytes, differential gene expression analysis showed the gastric metaplasia-associated glycoprotein Deleted in Malignant Brain Tumors 1 (DMBT1) is highly upregulated by C. difficile. Surprisingly, our spatial transcriptomic analysis showed DMBT1 was dramatically downregulated in dysplastic foci compared with normal-appearing tissue. We show that DMBT1 protein is downregulated in 100% of dysplastic foci across 3 different mouse models of colonic tumorigenesis: C. difficile-associated tumorigenesis in ApcMin/+, azoxymethane/dextran sodium sulfate, and Lrig1CreER/+;Apcfl/+ mice (n = 57 foci from 11 mice). Immunofluorescent staining of DMBT1 is markedly downregulated compared with normal adjacent crypts. Using scRNA-seq data and tissue microscopy in human CRC, we confirmed the same pattern of downregulated DMBT1 expression in dysplastic crypts compared with normal-appearing crypts. We present data from a human mucosal biofilm-associated colonic tumorigenesis murine model at single-cell resolution to reveal interesting cell type-specific transitions and generalizable mechanisms of tumorigenesis. We hypothesize that DMBT1 is a component of the gut epithelial response to pathogens and a critical regulator of proliferation and differentiation during post-injury restitution. We are now functionally testing how the loss of DMBT1 impacts tumorigenesis using human organoids. Ultimately, these studies aim to reveal novel biomarkers and/or targets for therapeutic intervention in CRC. Citation Format: Emily H. Green, Subhag R. Kotrannavar, Megan E. Rutherford, Harsimran Kaur, Hannah M. Lunnemann, Cody N. Heiser, Shaoguang Wu, Hua Ding, J. Alan Simmons, Xiao Liu, D. Borden Lacy, Martha J. Shrubsole, Qi Liu, Ken S. Lau, Cynthia L. Sears, Robert J. Coffey, Julia L. Drewes, Nicholas O. Markham. Deleted in malignant brain tumors 1 (DMBT1) glycoprotein is lost in colonic dysplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6693.