p53 mutation biases squamocolumnar junction progenitor cells towards dysplasia rather than metaplasia in Barrett's oesophagus

Guodong Lian; Ermanno Malagola; Chengguo Wei; Qiongyu Shi; Junfei Zhao; Masahiro Hata; Hiroki Kobayashi; Yosuke Ochiai; Biyun Zheng; Xiaofei Zhi; Feijing Wu; Ruhong Tu; Osmel Companioni Nápoles; Wenjing Su; Leping Li; Changqing Jing; Man Chen; Leah Zamechek; Richard Friedman; Karol Nowicki-Osuch; Michael Quante; Jianwen Que; Timothy C Wang

doi:10.1136/gutjnl-2024-332095

p53 mutation biases squamocolumnar junction progenitor cells towards dysplasia rather than metaplasia in Barrett's oesophagus

Gut. 2024 Oct 1:gutjnl-2024-332095. doi: 10.1136/gutjnl-2024-332095. Online ahead of print.

Authors

Guodong Lian^{1

2

3}, Ermanno Malagola¹, Chengguo Wei⁴, Qiongyu Shi^{1

5}, Junfei Zhao⁶, Masahiro Hata¹, Hiroki Kobayashi¹, Yosuke Ochiai¹, Biyun Zheng¹, Xiaofei Zhi¹, Feijing Wu¹, Ruhong Tu¹, Osmel Companioni Nápoles¹, Wenjing Su⁷, Leping Li^{2

3}, Changqing Jing^{2

3}, Man Chen^{4

8

9}, Leah Zamechek¹, Richard Friedman¹⁰, Karol Nowicki-Osuch^{11

12}, Michael Quante¹³, Jianwen Que¹⁴, Timothy C Wang^{15

16}

Affiliations

¹ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
² Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
³ Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
⁴ Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Biostatistics, Columbia University Mailman School of Public Health, New York, NY, USA.
⁶ Department of Systems Biology, Columbia University, New York, NY, USA.
⁷ Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
⁸ Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
⁹ Department of Critical Care Medicine, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
¹⁰ Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA.
¹¹ German Cancer Research Center (DKFZ) Heidelberg, Tumorigenesis and Molecular Cancer Prevention Group, Heidelberg, Germany.
¹² Herbert and Florence Irving Institute for Cancer Dynamics, Columbia University, New York, NY, USA.
¹³ Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Munchen, Germany.
¹⁴ Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY, USA.
¹⁵ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA [email protected].
¹⁶ Columbia University Digestive and Disease Research Center, New York, NY, USA.

PMID: 39353725
DOI: 10.1136/gutjnl-2024-332095

Abstract

Background: While p53 mutations occur early in Barrett's oesophagus (BE) progression to oesophageal adenocarcinoma (EAC), their role in gastric cardia stem cells remains unclear.

Objective: This study investigates the impact of p53 mutation on the fate and function of cardia progenitor cells in BE to EAC progression, particularly under the duress of chronic injury.

Design: We used a BE mouse model (L2-IL1β) harbouring a Trp53 mutation (R172H) to study the effects of p53 on Cck2r⁺ cardia progenitor cells. We employed lineage tracing, pathological analysis, organoid cultures, single-cell RNA sequencing (scRNA-seq) and computational analyses to investigate changes in progenitor cell behaviour, differentiation patterns and tumour progression. Additionally, we performed orthotopic transplantation of sorted metaplastic and mutant progenitor cells to assess their tumourigenic potential in vivo.

Results: The p53 mutation acts as a switch to expand progenitor cells and inhibit their differentiation towards metaplasia, but only amidst chronic injury. In L2-IL1β mice, p53 mutation increased progenitors expansion and lineage-tracing with a shift from metaplasia to dysplasia. scRNA-seq revealed dysplastic cells arise directly from mutant progenitors rather than progressing through metaplasia. In vitro, p53 mutation enhanced BE progenitors' organoid-forming efficiency, growth, DNA damage resistance and progression to aneuploidy. Sorted metaplastic cells grew poorly with no progression to dysplasia, while mutant progenitors gave rise to dysplasia in orthotopic transplantation. Computational analyses indicated that p53 mutation inhibited stem cell differentiation through Notch activation.

Conclusions: p53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia.

Keywords: BARRETT'S METAPLASIA; BARRETT'S OESOPHAGUS; DYSPLASIA; OESOPHAGEAL CANCER; STEM CELLS.

Grants and funding

R01 DK132251/DK/NIDDK NIH HHS/United States