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Human colorectal pre-cancer atlas identifies distinct molecular programs underlying two major subclasses of pre-malignant tumors

View ORCID ProfileBob Chen, View ORCID ProfileEliot T. McKinley, View ORCID ProfileAlan J. Simmons, Marisol A. Ramirez-Solano, View ORCID ProfileXiangzhu Zhu, View ORCID ProfileAustin N. Southard-Smith, View ORCID ProfileNicholas O. Markham, View ORCID ProfileQuanhu Sheng, View ORCID ProfileJulia L. Drewes, Yanwen Xu, View ORCID ProfileCody N. Heiser, Yuan Zhou, Frank Revetta, View ORCID ProfileLynne Berry, Wei Zheng, View ORCID ProfileM. Kay Washington, View ORCID ProfileQiuyin Cai, View ORCID ProfileCynthia L. Sears, View ORCID ProfileJames R. Goldenring, View ORCID ProfileJeffrey L. Franklin, View ORCID ProfileSimon Vandekar, View ORCID ProfileJoseph T. Roland, View ORCID ProfileTimothy Su, Won Jae Huh, Qi Liu, View ORCID ProfileRobert J. Coffey, View ORCID ProfileMartha J. Shrubsole, View ORCID ProfileKen Lau
doi: https://doi.org/10.1101/2021.01.11.426044
Bob Chen
1Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville TN
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
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Eliot T. McKinley
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
3Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville TN
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Alan J. Simmons
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
3Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville TN
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Marisol A. Ramirez-Solano
4Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville TN
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Xiangzhu Zhu
5Vanderbilt Ingram Cancer Center, Nashville, TN
6Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville TN
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Austin N. Southard-Smith
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
3Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville TN
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Nicholas O. Markham
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
7Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville TN
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Quanhu Sheng
4Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville TN
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Julia L. Drewes
8Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore MD
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Yanwen Xu
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
3Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville TN
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Cody N. Heiser
1Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville TN
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
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Yuan Zhou
4Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville TN
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Frank Revetta
9Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN
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Lynne Berry
4Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville TN
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Wei Zheng
5Vanderbilt Ingram Cancer Center, Nashville, TN
6Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville TN
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M. Kay Washington
9Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN
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Qiuyin Cai
5Vanderbilt Ingram Cancer Center, Nashville, TN
6Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville TN
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Cynthia L. Sears
8Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore MD
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  • ORCID record for Cynthia L. Sears
James R. Goldenring
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
5Vanderbilt Ingram Cancer Center, Nashville, TN
10Department of Surgery, Vanderbilt University Medical Center, Nashville TN
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Jeffrey L. Franklin
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
7Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville TN
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Simon Vandekar
4Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville TN
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Joseph T. Roland
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
10Department of Surgery, Vanderbilt University Medical Center, Nashville TN
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Timothy Su
6Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville TN
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Won Jae Huh
9Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN
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Qi Liu
4Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville TN
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Robert J. Coffey
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
5Vanderbilt Ingram Cancer Center, Nashville, TN
8Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore MD
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  • For correspondence: robert.coffey@vumc.org martha.shrubsole@vumc.org ken.s.lau@vanderbilt.edu
Martha J. Shrubsole
5Vanderbilt Ingram Cancer Center, Nashville, TN
6Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville TN
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  • For correspondence: robert.coffey@vumc.org martha.shrubsole@vumc.org ken.s.lau@vanderbilt.edu
Ken Lau
1Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville TN
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN
3Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville TN
5Vanderbilt Ingram Cancer Center, Nashville, TN
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  • For correspondence: robert.coffey@vumc.org martha.shrubsole@vumc.org ken.s.lau@vanderbilt.edu
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Abstract

Most colorectal cancers (CRCs) develop from either adenomas (ADs) or sessile serrated lesions (SSLs). The origins and molecular landscapes of these histologically distinct pre-cancerous polyps remain incompletely understood. Here, we present an atlas at single-cell resolution of sporadic conventional tubular/tubulovillous ADs, SSLs, hyperplastic polyps (HPs), microsatellite stable (MSS) and unstable (MSI-H) CRC, and normal colonic mucosa. Using single-cell transcriptomics and multiplex imaging, we studied 69 datasets from 33 participants. We also examined separate sets of 66 and 274 polyps for RNA and targeted gene sequencing, respectively. We performed multiplex imaging on a tissue microarray of 14 ADs and 15 CRCs, and we integrated pre-cancer polyp data with published single-cell and The Cancer Genome Atlas (TCGA) bulk CRC data to establish potential polyp-cancer relationships. Striking differences were observed between ADs and SSLs that extended to MSS and MSI-H CRCs, respectively, reflecting their distinct origins and trajectories. ADs arose from WNT pathway dysregulation in stem cells, which aberrantly expanded and expressed a Hippo and ASCL2 regenerative program. In marked contrast, SSLs were depleted of stem cell-like populations and instead exhibited a program of gastric metaplasia in the setting of elevated cytotoxic inflammation. Using subtype-specific gene regulatory networks and shared genetic variant analysis, we implicated serrated polyps, including some HPs conventionally considered benign, as arising from a metaplastic program in committed absorptive cells. ADs and SSLs displayed distinct patterns of immune cell infiltration that may influence their natural history. Our multi-omic atlas provides novel insights into the malignant potential of colorectal polyps and serves as a framework for precision surveillance and prevention of sporadic CRC.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Human colorectal pre-cancer atlas identifies distinct molecular programs underlying two major subclasses of pre-malignant tumors
Bob Chen, Eliot T. McKinley, Alan J. Simmons, Marisol A. Ramirez-Solano, Xiangzhu Zhu, Austin N. Southard-Smith, Nicholas O. Markham, Quanhu Sheng, Julia L. Drewes, Yanwen Xu, Cody N. Heiser, Yuan Zhou, Frank Revetta, Lynne Berry, Wei Zheng, M. Kay Washington, Qiuyin Cai, Cynthia L. Sears, James R. Goldenring, Jeffrey L. Franklin, Simon Vandekar, Joseph T. Roland, Timothy Su, Won Jae Huh, Qi Liu, Robert J. Coffey, Martha J. Shrubsole, Ken Lau
bioRxiv 2021.01.11.426044; doi: https://doi.org/10.1101/2021.01.11.426044
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Human colorectal pre-cancer atlas identifies distinct molecular programs underlying two major subclasses of pre-malignant tumors
Bob Chen, Eliot T. McKinley, Alan J. Simmons, Marisol A. Ramirez-Solano, Xiangzhu Zhu, Austin N. Southard-Smith, Nicholas O. Markham, Quanhu Sheng, Julia L. Drewes, Yanwen Xu, Cody N. Heiser, Yuan Zhou, Frank Revetta, Lynne Berry, Wei Zheng, M. Kay Washington, Qiuyin Cai, Cynthia L. Sears, James R. Goldenring, Jeffrey L. Franklin, Simon Vandekar, Joseph T. Roland, Timothy Su, Won Jae Huh, Qi Liu, Robert J. Coffey, Martha J. Shrubsole, Ken Lau
bioRxiv 2021.01.11.426044; doi: https://doi.org/10.1101/2021.01.11.426044

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