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Introduction

The gastric epithelial gland homeostasis is driven by insufficiently characterized sub-epithelial stromal signals. Gastric stem cells in the gland base are fueled by a Wnt/Rspo^high niche where Bmp activity is suppressed, while terminally differentiated mucous pit cells are maintained by a BMP^high niche, that suppresses Wnt/Rspo activity. Infection with Helicobacter pylori reduces stromal and epithelial Bmp activity driving stem cell expansion. In line with this, genetic knockout of BMP activity in the epithelium leads to epithelial hyperplasia. The consequences of loss of BMP activity in the stroma on epithelial homeostasis and proliferative, regenerative, and inflammatory pathways in the interplay between stroma and epithelium are unknown.

Aims & Methods

The objective of this study was to analyze the epithelial pathology and epithelial-stromal interplay in the context of loss of BMP activity in the gastric stroma by using an inducible knockout of the BMP type 1 receptor in the stroma in mice.

Results

After two months of knockout of the BMP receptor in the gastric stroma, mice display drastic hyperplasia via stem cell expansion in the antrum and the corpus. Loss of stromal BMP signaling causes the occurrence of a bulky stroma with expanded fibroblasts and aberrant glands within the pit area, that resemble the gland base with expression of stem cell factors, high proliferation, enhanced epithelial inflammation (marked by NF-κB p65) and expression of metaplasia markers (CD44v9, Aqp5). Using scRNAseq as well as organoid and assembloid technologies we now study the mechanisms by which loss of stromal BMP affects epithelial homeostasis.

Conclusion

Collectively, our data demonstrate that alterations in stromal BMP activity can promote premalignant lesions. This model will allow us to study the underlying principles of stromal-epithelial interplay in the stomach and explore mechanistically the consequences of stromal responses observed upon H. pylori infection in detail.

LOSS OF STROMAL BMP ACTIVITY DRIVES GASTRIC PATHOLOGY IN MICE

Jonas Wizenty 1, Michael Sigal 1

1 Charité - Universitätsmedizin Berlin, Berlin, Germany

Conference

UEG Week Vienna 2024

Topics

Oesophagus

Submission format

Abstract

Session

OESOPHAGEAL, GASTRIC AND DUODENAL (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Gastric diseases

Byron Cryer 1

1 University of Texas Southwestern Medical Center, Texas, United States of America

Event

UEG Week Vienna 2024

Topics

Endoscopy Gut Microbiota IBD Oesophagus Stomach & H. Pylori

Session

Best of DDW

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Introduction

Helicobacter pylori (H.pylori) infection is the main risk factor for gastric cancer. Infection leads to chronic inflammation and gastric gland hyperplasia. We found that infection induces alterations in the stromal niche, such as inhibited secretion of BMP ligands and increased expression of BMP inhibitors. BMP signaling is known to be involved in differentiation of base progenitor cells into pit secretory cells. However, whether it plays a role in regulating mucosal antimicrobial defense is still unknown and we now investigate how the downregulation of BMP signaling affects mucosal inflammatory responses.

Aims & Methods

Exploiting in vivo murine models as well as in vitro assays, we aim to investigate how the downregulation of epithelial BMP signaling affects mucosal homeostasis.
3D gastric organoids were used to explore the role of BMP in epithelial responses to microbial proteins (qPCR, Western Blotting). The effects of epithelial BMP downregulation and stromal Il1r1 signaling were investigated by exploiting conditional knockout mice (Axin2CreERT2-Bmpr1afl/fl or Bmpr1a KO; Col1a2CreERT2-Il1r1fl/fl or Il1r1 KO) either uninfected or infected with H.pylori PMSS1. Tissue samples were analyzed via immunofluorescence, RNA-in situ hybridization and gene expression analysis (qPCR, whole transcriptome). 2D primary murine stromal cell culture were exploited to investigate stromal responses to inflammatory triggers.

Results

Exploiting 3D organoids, we demonstrate that epithelial cells activate NF-κB signaling in response to microbe-derived proteins, while this effect is inhibited upon BMP signaling activation. In vivo, inhibition of BMP signaling in the epithelium via knockout of Bmpr1a (Bmpr1a KO) not only causes gland hyperplasia but also strongly enhances inflammation at the pit of gastric glands, where it is absent in mice with functional BMP signaling. We explore the consequences of increased inflammation upon epithelial Bmpr1a KO, demonstrating via whole transcriptome analysis that this is linked to enhanced antimicrobial tissue responses and that KO mice show reduced H.pylori colonization. Moreover, we discover that the influx of IL-1β producing cells observed upon BMP signaling downregulation has an impact on stromal cells, which in turn produce pro-regenerative factors causing epithelial reprogramming into a highly proliferative fetal-like regenerative state. We demonstrate that Il1r1 KO mice, where stromal cells lack the ability to respond to IL-1β, do not show fetal-like reprogramming and are more colonized by H.pylori.

Conclusion

Chronic H.pylori infection causes tissue reprogramming into a fetal-like state via a crosstalk between epithelial, stromal and immune cells. This state is linked to an enhanced proinflammatory response, increased proliferation and boosters antimicrobial defense. We propose that long-term activation of this state may enhance the risk for malignant transformation.

HELICOBACTER PYLORI INFECTION CAUSES GASTRIC MUCOSAL REPROGRAMMING INTO A PROINFLAMMATORY, FETAL-LIKE STATE

Giulia Beccaceci 1, Stefanie Müllerke 1, Hilmar Berger 2, Christian Täger 3, Anne-Sophie Fischer 2, Jonas Wizenty 2, Kimberly Hartl 2, Hans-Joachim Mollenkopf 4, Michael Naumann 3, Manqiang Lin 5, Michael Sigal 1

1 Charité Universitätsmedizin Berlin, Berlin, Germany|||Berlin Institute for Medical Systems Biology (BIMSB) - Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany

2 Charité Universitätsmedizin Berlin, Berlin, Germany

3 Institute of Experimental Internal Medicine, Magdeburg, Germany

4 Max Planck Institute for Infection Biology, Berlin, Germany

5 Berlin Institute for Medical Systems Biology (BIMSB) - Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany|||Charité Universitätsmedizin Berlin, Berlin, Germany

Conference

UEG Week Berlin 2025

Topics

Stomach & H. Pylori

Submission format

Abstract

Session

DDM SUMMIT (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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ENDOSCOPIC RESECTION FOR GASTRIC GASTROINTESTINAL STROMAL TUMORS WITH DETACHABLE SNARE

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Introduction

Gastric Gastrointestinal Stromal Tumors (GISTs) are among the most common mesenchymal tumors arising in the gastrointestinal tract. Despite many international guidelines, the treatment of GISTs with tumor diameters less than 50 mm remains controversial. Although surgical resection is indicated for histologically diagnosed GISTs, endoscopic resection has recently been reported. However, endoscopic resection, mainly Endoscopic submucosal dissection (ESD), often requires a full-layer resection of the gastric wall, which requires extensive suturing. Therefore, we have developed an ESD technique for endoscopic resection of the gastric wall that uses a threaded clip and a detachable snare to strangulate the muscle layer prior to resection and allows safe and easy complete resection without perforation (EISMR: Endoscopic inversion and strangulation of the muscle layer and resection). We now report seven cases of EISMR for gastric GISTs.

Aims & Methods

We evaluated the safety and efficacy of EISMR for GISTs. Seven gastric GISTs (4 males and 3 females) with tumor diameters of 50 mm or less for which we performed EISMR were included in this study, and the en bloc resection rate, R0 resection rate, procedure time, and complications were investigated. All patients underwent EUS and abdominal CT scan before treatment to confirm that the pathological diagnosis was GIST, that the tumor diameter was less than 50 mm, and that the tumor was intraluminal growth type.
In the EISMR procedure, sodium hyaluronate solution was first injected into the submucosal layer of the lesion to dissect the submucosa as in ESD. After a yellowish GIST continuity with the muscularis propria is observed, the submucosa and muscle layer are dissected to expose as much of the submucosa as possible without damaging the tumor. Next, a threaded clip is attached to the tumor and pulled in order to invert the muscle layer. The muscle layer is then retracted into the gastric lumen to form a polyp-like shape, and the base of the muscle layer is strangulated using an detachable snare (PolyLoop Ligating Device, Olympus). The upper margin of the strangulated area is then incised to complete the resection. After confirming that there is no perforation, the strangulated area is additionally sutured with a clip.

Results

All seven cases could be resected en bloc, with a median time of 90.5 minutes (58-120). Of the seven EISMR cases, five cases were performed by experts and two by non-experts. All patients were discharged on postoperative day 5 or 6 without adverse events. Pathology results showed complete resection in the low-risk GIST group. Upper endoscopy 3-6 months after EISMR showed no tumor recurrence and only scarring.

Conclusion

EISMR for gastric GISTs is potentially safe, easy and useful without excessive invasion.

ENDOSCOPIC RESECTION FOR GASTRIC GASTROINTESTINAL STROMAL TUMORS WITH DETACHABLE SNARE

Masahiro Takeo 1, Takeshi Yamashina 1, Masaaki Shimatani 1, Hironao Matsumoto 1, Makoto Naganuma 2

1 Kansai Medical University Medical Center, Moriguchi, Japan

2 Kansai Medical University 3rd Dept. of Internal Medicine, Hirakata, Japan

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Endoscopy Oesophagus

Submission format

Video Case

Session

Video Case Session: Third space endoscopy

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Introduction

Helicobacter pylori is the main risk factor for gastric cancer, but only 1 to 5% of infected individuals develop gastric cancer, suggesting that additional factors are required. The Rspo3/Wnt signaling pathway is essential for the proliferation and self-renewal of stem cells and controls gastric epithelial differentiation. 50% of gastric cancer samples show aberration of Rspo3/Wnt signaling.

Aims & Methods

We hypothesize that the pro-carcinogenic potential of infection with Helicobacter pylori is context-dependent and that synergistic effects of Rspo3/Wnt signaling and infection-specific tissue responses drive carcinogenesis. We aim to mechanistically dissect this interplay.
Using conditional mouse models enabling the up- and downregulation of Rspo3 in stromal myofibroblasts and infecting them with Helicobacter pylori, we analyze the role of stromal signaling in Helicobacter pylori-driven carcinogenesis. In addition, we apply a new conditional mouse model enabling the stomach-specific epithelial knockout of the Wnt antagonist Apc to understand the contribution of epithelial Wnt mutation to epithelial behavior and identity and stromal signaling in non-infected and Helicobacter pylori-infected mice. Methodologically, we apply immunofluorescence staining followed by quantitative and spatial analyses and single-cell RNA sequencing, microarray analyses, and gene set enrichment analyses to discover gene expression patterns, dissect cellular heterogeneity, and identify central driver pathways. Using 3D organoid models, we investigate the mechanisms promoting epithelial proliferation and malignant transformation in the context of infection with Helicobacter pylori. We verify the murine results by immunohistological analyses of human gastric cancer tissue.

Results

We find that infection with Helicobacter pylori induces epithelial reprogramming into a regenerative fetal-like state characterized by hyperproliferation and the activation of YAP signaling. Reprogramming depends on stromal Rspo3 signaling. In mice that overexpress Rspo3, chronic Helicobacter pylori-driven inflammation locks the epithelium in the regenerative state, promoting metaplastic changes. Knockout of Rspo3 blocks this response. Rspo3 also promotes the infiltration of immune cells into the tissue, which further perpetuates pathology. Interestingly, infected Rspo3 overexpressing mice show a significantly higher number of PD-L1 positive cells than infected wild-type mice. We confirm the positive correlation between Rspo3 and PD-L1 expression in tissue microarrays of 240 gastric cancers.
Consistent with previous murine and clinical data, knockout of Apc in epithelial cells does not lead to gastric cancer in the absence of infection with Helicobacter pylori. In contrast, infected Apc knockout mice develop carcinogenic lesions after 2 months. Immunofluorescence labeling, single-cell RNA sequencing, and microarray analyses reveal an infection-dependent remodeling of the epithelial niche in Apc knockout mice.

Conclusion

Together, we discover that cell-intrinsic Wnt signaling synergizes with cell-extrinsic infection-driven alterations of the niche to drive tissue reprogramming and carcinogenic transformation. This work demonstrates the crucial interaction of genetic and environmental factors in gastric carcinogenesis.

SYNERGISMS OF HELICOBACTER PYLORI-DRIVEN TISSUE REPROGRAMMING AND RSPO3/WNT SIGNALING IN GASTRIC CARCINOGENESIS

Anne-Sophie Fischer 1, Stefanie Müllerke 1, Alexander Arnold 1, Julian Heuberger 2, Hilmar Berger 1, Manqiang Lin 1, Hans-Joachim Mollenkopf 3, Jonas Wizenty 1, David Horst 1, Frank Tacke 1, Michael Sigal 4

1 Charité Universitätsmedizin Berlin, Berlin, Germany

2 Charité Universitätsmedizin Berlin, Berlin, Germany|||Bundesinstitut für Risikobewertung, Berlin, Germany

3 Max Planck Institute for Infection Biology, Berlin, Germany

4 Charité Universitätsmedizin Berlin, Berlin, Germany|||Max Delbrück Center - Berlin Institute for Medical Systems Biology (MDC-BIMSB), Berlin, Germany

Conference

UEG Week Berlin 2025

Topics

Stomach & H. Pylori

Submission format

Abstract

Session

DDM SUMMIT (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Introduction

Gastric chief cells can re-enter the cell cycle after injury through paligenosis, a conserved regenerative program regulated by mTORC1. This process involves (1) cellular degradation, (2) induction of progenitor genes (spasmolytic polypeptide-expressing metaplasia, SPEM), and (3) cell cycle re-entry. Dysregulated paligenosis contributes to gastric cancer, but mechanisms governing this reprogramming remain incompletely understood. Here, we investigated the role and regulation of YAP1, a key effector of the Hippo pathway, during paligenosis.

Aims & Methods

Our objectives were to determine whether YAP1 is activated during paligenosis, define its role, and identify upstream regulators. Using a mouse model of injury-induced paligenosis (via high-dose tamoxifen, HDTAM, intraperitoneal injection), we analyzed YAP1 activation and Hippo pathway dynamics via proteomics, single-cell RNA sequencing, western blot, immunohistochemistry, and immunofluorescence. To dissect upstream signaling, we employed a series of genetically engineered mouse models targeting Hippo pathway components.

Results

YAP1 is rapidly activated (via dephosphorylation) during the early stage of paligenosis. Functional assays revealed that YAP1 (and its paralog, TAZ) are necessary and sufficient to drive chief cell reprogramming. Among upstream kinases, only STK38 activity mirrored YAP1 activation patterns. STK38 is essential for YAP1 activation and is degraded via autophagy during transition to stage 2. Notably, STK38 harbors a UFM1/LC3-interacting region (LIR) domain and is targeted to autophagosomes. We found that MIST1 induces UFM1, which protects STK38 from autophagic degradation. In Mist1^−/⁻mice, reduced UFM1 correlates with heightened basal autophagy, STK38 loss, and constitutive YAP1 activation. Furthermore, STK38 interacts with NF2, similar to canonical Hippo kinases, modulating YAP1 regulation.

Conclusion

We identify a novel MIST1–UFM1–STK38 axis that regulates YAP1 activity in an autophagy-dependent manner during paligenosis. STK38 acts as a non-canonical Hippo kinase whose stability dictates YAP1 activation. These findings uncover new layers of Hippo pathway regulation and highlight the dynamic control of YAP1 during gastric epithelial regeneration.

THE MIST1–UFM1–STK38 AXIS REGULATES YAP1 ACTIVITY TO ENABLE PROGENITOR-LIKE REPROGRAMMING OF GASTRIC CHIEF CELLS DURING PALIGENOSIS

Yongji Zeng 1, Yang-Zhe Huang 1, Raymond Ho 1, Steven Bark 2, Jason Mills 2

1 Baylor College of Medicine, Houston, United States

2 Baylor College of Medicine, Houston, United States|||Baylor College of Medicine, Houston, United States

Conference

UEG Week Berlin 2025

Topics

Oesophagus

Submission format

Abstract

Session

Back to the basics of gastric cancer (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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ENDOSCOPIC PEDICLE FLAP CLOSURE AFTER FULL-THICKNESS GASTRIC RESECTION OF GASTROINTESTINAL STROMAL TUMOR

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Introduction

A 52-year-old man was found to have a gastric submucosal protrusion lesion approximately 3.0 cm in size at the gastric antrum when he underwent gastroscopy. Endosonography and computerized tomography confirmed a gastrointestinal stromal tumor (GIST) originating from the muscularis propria with trans-mural growth.

Aims & Methods

Based on the growth pattern, endoscopic full-thickness resection(EFTR) was performed to enucleate the tumor. After submucosal injection, the mucosa near the lesion was dissected and used as a pedicle flap. Separated the lesion gradually and completely removed the tumor along the capsule to avoid intraperitoneal dissemination. Full-thickness resection leaved a large defect. Using purse-string suture to close the wound with a nylon rope and eight clips. And covered with a pedicle flap using four clips for reliable closure.

Results

The resection time was 44 minutes and the suture time was 16 minutes. The patient had no adverse events during the operation. Histopathology confirmed that it is a low risk g-GIST. The patient was discharged 5 days later without any significant discomfort. After 4 months, Gastroscopy showed complete healing.

Conclusion

Pedicle flap grafting can increase the safety of nylon rope suturing. Therefore, endoscopic pedicle flap grafting can be considered as an optional closure method for full-thickness defect after EFTR.

ENDOSCOPIC PEDICLE FLAP CLOSURE AFTER FULL-THICKNESS GASTRIC RESECTION OF GASTROINTESTINAL STROMAL TUMOR

Pinghua Wen 1, Yi Mou 1, Bing Hu 1

1 West China Hospital,Sichuan University, Chengdu, China

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Endoscopy Oesophagus

Submission format

Video Case

Session

Video Case Session: Third space endoscopy

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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