Gastroenterology TUM

23/06/2025

More : "Activation of RAS/MEK/ERK signalling drives biliary differentiation in primary liver " ist our in Gut / BMJ Journals. Congratulations to our team!

https://gut.bmj.com/content/early/2025/05/12/gutjnl-2024-333238

Thomas Rösner, Carina Rupp, Christian Lechler, Ulrike Bauer, Saumya Sukumary Manmadhan, Sophia Bernatik, Fabian Delugré, Franziska Ihli, Tanja Derowski, Simone Jörs, Birgit Kohnke-Ertel, Henrik Einwächter, Nicole Pfarr, Katja Steiger, Carolin Mogler, Maximilian Reichert, Dieter Saur, Diana Becker, Jens U Marquardt, Rupert Öllinger, Thomas Engleitner, Roland Rad, Roland M Schmid, Ursula Ehmer

Abstract:

Background:
RAS mutations are frequently observed in human cholangiocarcinoma (CCA), while they are relatively rare in hepatocellular carcinoma (HCC). The role of RAS-dependent signalling pathways in CCA development is currently not well understood.

Objective:
The objective of this study was to investigate RAS-dependent signalling pathways in CCA and their role in tumour development and differentiation.

Design:
We used genetically engineered mouse models with liver-specific deletion of tumour suppressors Rb and p53 together with activation of oncogenic Kras to investigate the cell of origin in intrahepatic CCA and to elucidate the role of RAS-dependent signalling pathways in CCA development.

Results:
In mice, Kras-mutant intrahepatic CCA develops primarily from hepatocytes and shows activation of PI3K/AKT and MEK/ERK signalling downstream of KRAS. Targeted genetic inactivation of each of these pathways leads to delayed tumour growth and profound alterations in tumour differentiation. Specifically, reduced PI3K/AKT signalling promotes more well-differentiated tumours, whereas the inactivation of MEK/ERK signalling induces a differentiation switch towards a more hepatocyte-like phenotype. This switch is accompanied by activation of WNT/β-catenin signalling, a pathway commonly activated in human HCC.

Conclusions:
These findings provide insights into the role of RAS-dependent pathways in liver cancer differentiation and offer a compelling explanation for the high prevalence of RAS mutations in human CCA compared with HCC.

TU München

Background RAS mutations are frequently observed in human cholangiocarcinoma (CCA), while they are relatively rare in hepatocellular carcinoma (HCC). The role of RAS-dependent signalling pathways in CCA development is currently not well understood. Objective The objective of this study was to invest...

23/06/2025

Proud to announce our in Nature : "Evolutionary and immune microenvironment dynamics during neoadjuvant treatment of esophageal adenocarcinoma".

https://www.nature.com/articles/s43018-025-00955-w

Melissa Barroux, Jacob Househam, Eszter Lakatos, Tahel Ronel, Ann-Marie Baker, Henrike Salié, Maximilian Mossner, Kane Smith, Chris Kimberley, Salpie Nowinski, Alison Berner, Vinaya Gunasri, Martin Borgmann, Sven Liffers, Marnix Jansen, Giulio Caravagna, Katja Steiger, Julia Slotta-Huspenina, Wilko Weichert, Luis Zapata, Eleftheria Giota, Sylvie Lorenzen, Markus Alberstmeier, Benny Chain, Helmut Friess, Bertram Bengsch, Roland M. Schmid, Jens T. Siveke, Michael Quante & Trevor A. Graham

Abstract:
Locally advanced esophageal adenocarcinoma remains difficult to treat and the ecological and evolutionary dynamics responsible for resistance and recurrence are incompletely understood. Here, we performed longitudinal multiomic analysis of patients with esophageal adenocarcinoma in the MEMORI trial. Multi-region multi-timepoint whole-exome and paired transcriptome sequencing was performed on 27 patients before, during and after neoadjuvant treatment.

We found major transcriptomic changes during treatment with upregulation of immune, stromal and oncogenic pathways. Genetic data revealed that clonal sweeps through treatment were rare. Imaging mass cytometry and T cell receptor sequencing revealed remodeling of the tumor microenvironment during treatment. The presence of genetic immune escape, a less-cytotoxic T cell phenotype and a lack of clonal T cell expansions were linked to poor treatment response.

In summary, there were widespread transcriptional and environmental changes through treatment, with limited clonal replacement, suggestive of phenotypic plasticity.

TU München #

Graham and colleagues analyzed locally advanced esophageal adenocarcinoma clinical trial patient samples and identified major changes in gene expression profiles and immune microenvironment composition independent of changes in clonal composition.

21/05/2025

Wer stirbt an , wer überlebt? Was haben die "Super Survivor" - Überlebende aggressiver Krebsarten - gemeinsam? Das soll mit der neuen, weltweiten - herausgefunden werden. Molekulare Daten von mehr als 1.000 Krebsüberlebenden werden einfließen.

Die TU München wird federführend die Daten von Menschen mit Bauchspeicheldrüsenkarzinom betreuen. Aufgrund der sehr geringen Überlebensrate bei sei die Studie für unser Münchner Forschungsteam so interessant, erklärt Prof. Maximilian , Leiter des Zentrums für Translationale Pankreaskarzinomforschung an der , im Stern:

https://www.stern.de/gesundheit/wer-ueberlebt-krebs--wer-stirbt-daran--studie-soll-gruende-untersuchen-35737684.html

Lesetipp.

TUM Klinikum Rechts der Isar

Einen aggressiven Krebs überleben nur wenige Menschen. Was haben sie gemeinsam? Charité und TU München wollen es in einer internationalen Studie untersuchen.

07/05/2025

"COVID-19 Disease Burden in the Omicron Variant-Dominated Endemic Phase: Insights from the ROUTINE-COV19 Study Using Real-World German Statutory Health Insurance Data" - this is our in Viruses, 2025 Mar 14;17(3):424. doi: 10.3390/v17030424.

https://pubmed.ncbi.nlm.nih.gov/40143351/

Congratulations to the team!

Sabrina Müller, Andrea Schmetz, Julia K Knaul, Thomas Wilke, Jingyan Yang, Sabine Dornig, Clara Lehmann, Christoph D Spinner

Abstract

The ROUTINE-COV19 study explores the burden of -19 in Germany during the early endemic phase, assessing disease patterns and their impact on the healthcare system from 1 July 2022 to 30 June 2023. Using anonymized statutory health insurance data from over 3 million individuals in Thuringia and Saxony, COVID-19 cases were identified through diagnostic codes, with severe and critical cases defined by hospitalization and intensive care criteria.

The focused on high-risk populations as identified by the German Immunization Technical Advisory Group. During the study period, 414,648 new COVID-19 cases were documented, with peaks in October 2022 and March 2023. Severe cases occurred at a rate of 241.6 per 100,000 persons, with in-hospital mortality exceeding 12%. Critical cases requiring intensive care had an in-hospital mortality rate of 32.2%. COVID-19-related hospitalizations averaged 9.94 days, generating direct costs of EUR 64.9 million, while indirect costs from work absenteeism amounted to EUR 454.3 million, representing 7.5% of all-cause absenteeism costs. Despite entering an endemic phase, COVID-19 continues to pose a substantial burden, particularly among older adults and those with pre-existing cardiovascular conditions.

National Library of Medicine (NLM) TU München

The ROUTINE-COV19 study explores the burden of COVID-19 in Germany during the early endemic phase, assessing disease patterns and their impact on the healthcare system from 1 July 2022 to 30 June 2023. Using anonymized statutory health insurance data from over 3 million individuals in Thuringia and....

06/05/2025

"Epithelial Genetic Muscarinic Receptor 3 Ablation Induces Sex-Specific Modulation of Colonic Intestinal Progenitor Cells and Response to Intestinal Injury" - this is our new in the "Journal of Crohns and Colitis" (JCC).

Congratulations to the whole team!

Mohab Ragab , Jessica Wieland , Caroline Waldherr Ávila de Melo , Tatiana Agibalova , Anastasia Ermolova , Niklas Durner , Anneke Hempel , Fabian Heindl , H Carlo Maurer , Katja Steiger , Klaus-Peter Janssen , Markus Tschurtschenthaler , Timothy C Wang , Michael Quante , Roland M Schmid , Moritz Middelhoff

Journal of Crohn's and Colitis, jjaf038, https://doi.org/10.1093/ecco-jcc/jjaf038

Abstract

Background & Aims:
Epithelial muscarinic acetylcholine receptor subtype 3 (M3R) signaling modulates intestinal stem and progenitor cell function, yet its impact on colonic homeostasis remains unclear. Hence, this study explores s*x-specific effects of epithelial genetic M3R ablation and muscarinic receptor agonism on murine colonic Lgr5-EGFP+ progenitor cells and epithelial homeostasis.

Methods:
Genetic ablation of M3R was achieved using Vil-Cre x M3R fl/fl mice. The effects on Lgr5-expressing progenitor cells, epithelial homeostasis and response to intestinal injury were assessed, with attention to s*x-specific differences. Effects of cholinergic, muscarinic agonism on epithelial cell homeostasis were evaluated employing murine and human colonoids.

Results:
Genetic epithelial ablation of the M3R employing Vil-Cre x M3R fl/fl mice interestingly resulted in the prominent reduction in Lgr5-expressing progenitor cells in male tissues, contrasting an expansion of Lgr5-expressing cells in female colonic epithelia. This difference showed abrogated in young female Vil-Cre x M3R fl/fl mice, which harbor reduced circulating s*x hormone levels. Genetic M3R ablation further induced changes to epithelial differentiation. Importantly, male Vil-Cre x M3R fl/fl mice developed severe inflammation following induction of acute experimental colitis, which did almost not affect female Vil-Cre x M3R fl/fl mice. Moreover, s*x-specific effects of modulations of cholinergic, muscarinic signaling on epithelial cells could be corroborated in murine and human colonoids.

Conclusions:
Our data reveal s*x differences in the modulation of intestinal, colonic epithelial cells by cholinergic, muscarinic signaling and highlight the potential for therapeutic strategies targeting cholinergic receptor signaling in colonic inflammatory diseases.

Fachschaft Medizin TUM TU München

AbstractBackground & Aims. Epithelial muscarinic acetylcholine receptor subtype 3 (M3R) signaling modulates intestinal stem and progenitor cell functio

13/03/2025

In his lecture 'Liver and bile duct lymphocyte dynamics in health and disease', Professor Niklas Björkström from the Karolinska Institutet illuminated the role of natural killer cells (NK cells) in the liver and bile duct system. Using state-of-the-art technologies such as MACSima, he has gained new insights into the dynamics and function of these immune cells in both healthy and diseased tissues.

These findings are helping to deepen our understanding of immune regulation in the liver and could, in the long term, contribute to the development of new therapeutic approaches for liver and bile duct diseases.

Thank you Professor Björkström for coming all the way to Munich to share your exciting science with us!

https://www.med2.mri.tum.de/en/seminar_series/index.php

TU München MGC Doctoral Candidates

11/03/2025

: "A decision point between transdifferentiation and programmed cell death priming controls -dependent pancreatic development"- this is our publication in "Nature Communications" / Nature Portfolio.

https://www.nature.com/articles/s41467-025-56493-7

Congratulations to the whole team!

Anne T. Schneider, Christiane Koppe, Emilie Crouchet, Aristeidis Papargyriou, Michael T. Singer, Veronika Büttner, Leonie Keysberg, Marta Szydlowska, Frank Jühling, Julien Moehlin, Min-Chun Chen, Valentina Leone, Sebastian Mueller, Thorsten Neuß, Mirco Castoldi, Marina Lesina, Frank Bergmann, Thilo Hackert, Katja Steiger, Wolfram T. Knoefel, Alex Zaufel, Jakob N. Kather, Irene Esposito, Matthias M. Gaida, Ahmed Ghallab, Jan G. Hengstler, Henrik Einwächter, Kristian Unger, Hana Algül, Nikolaus Gassler, Roland M. Schmid, Roland Rad, Thomas F. Baumert, Maximilian Reichert, Mathias Heikenwalder, Vangelis Kondylis, Mihael Vucur & Tom Luedd

Abstract:
KRAS-dependent acinar-to-ductal metaplasia (ADM) is a fundamental step in the development of pancreatic ductal adenocarcinoma (PDAC), but the involvement of cell death pathways remains unclear. Here, we show that key regulators of programmed cell death (PCD) become upregulated during KRAS-driven ADM, thereby priming transdifferentiated cells to death. Using transgenic mice and primary cell and organoid cultures, we show that transforming growth factor (TGF)-β-activated kinase 1 (TAK1), a kinase regulating cell survival and inflammatory pathways, prevents the elimination of transdifferentiated cells through receptor-interacting protein kinase 1 (RIPK1)-mediated apoptosis and necroptosis, enabling PDAC development. Accordingly, pharmacological inhibition of TAK1 induces PCD in patient-derived PDAC organoids. Importantly, cell death induction via TAK1 inhibition does not appear to elicit an overt injury-associated inflammatory response. Collectively, these findings suggest that TAK1 supports cellular plasticity by suppressing spontaneous PCD activation during ADM, representing a promising pharmacological target for the prevention and treatment of .

TU München MGC Doctoral Candidates

The involvement of cell death pathways in the early stage of pancreatic ductal adenocarcinoma (PDAC) development, especially KRAS-dependent acinar-to-ductal metaplasia (ADM), remains to be investigated. Here, the authors find that TAK1 mediates cell survival during ADM transdifferentiation through s...

03/02/2025

New Alert: Excited to share our work in Mol Syst Biol. / NCBI - National Center for Biotechnology Information. For why the combination of gemcitabine and ATR inhibition may be useful for the treatment of patients: https://pubmed.ncbi.nlm.nih.gov/39838187/

TU München

The DNA-damaging agent Gemcitabine (GEM) is a first-line treatment for pancreatic cancer, but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs, including kinase inhibitors, but the experimental evidence for such ration...

09/01/2025

Publication alert 👉 "Vasoactive intestinal peptide promotes secretory differentiation and mitigates radiation-induced intestinal injury" in Stem Cell Res Ther / NCBI - National Center for Biotechnology Information:
https://pmc.ncbi.nlm.nih.gov/articles/PMC11462795/

Results:
We observed that VIP promotes epithelial differentiation towards a secretory phenotype predominantly via the p38 MAPK pathway. Moreover, VIP prominently modulated epithelial proliferation as well as the number and proliferative activity of Lgr5-EGFP+ progenitor cells under homeostatic conditions. In the context of acute irradiation injury in vitro, we observed that IR injury renders Lgr5-EGFP+ progenitor cells more susceptible to VIP-induced modulations, which coincided with the strong promotion of epithelial regeneration by VIP. Finally, the observed effects translate into an in vivo model of abdominal irradiation, where VIP showed to prominently mitigate radiation-induced injury.

Conclusion:
VIP prominently governs intestinal homeostasis by regulating epithelial progenitor cell proliferation and differentiation and promotes intestinal regeneration following acute irradiation injury.

TU München

Vasoactive intestinal peptide (VIP) is a neuronal peptide with prominent distribution along the enteric nervous system. While effects of VIP on intestinal motility, mucosal vasodilation, secretion, and mucosal immune cell function are well-studied, ...

13/12/2024

"Foundation for new treatment strategies: Organoids represent the complex cell landscape of " // Congratulations to our team, led by Maximilian Reichert, Professor of Translational Pancreatic Cancer Research at the TUM University Hospital Klinikum rechts der Isar, to their success!

Press information by TU München:
A team led by researchers at the Technical University of Munich (TUM) has, for the first time, grown tumor organoids – three-dimensional miniature tumors in the laboratory – that mimic the different structures and characteristics of pancreatic cancer. The scientists investigated how the various tumor organoids react to established and novel treatments. This opens the door to the development of effective new therapies.

Pancreatic cancer ranks among the most lethal cancers, with an exceptionally high mortality rate. One of the reasons is the lack of efficacious treatments, since different cancer cells within the same tumor can react very differently to one and the same therapy. The cells of a pancreatic cancer tumor are highly diverse not only in terms of their structure, but also in their associated malignant properties, for example how aggressive they are.

Pancreatic cancer cells can be roughly divided into two main subtypes: epithelial and mesenchymal, based on their appearance and their molecular profile. "However, the tumor cells can change their structure and function during the course of the illness. It has been shown previously that a wide range of different manifestations exists within these two main categories. These can vary greatly in their biological characteristics," says Maximilian Reichert, Professor of Translational Pancreatic Cancer Research at the TUM University Hospital Klinikum rechts der Isar.
Complexity of pancreatic cancer reproduced in the laboratory

A team led by Reichert has now, for the first time, reproduced the morphological complexity of pancreatic cancer cell clusters in the laboratory. "Tumor cell clusters in the body are shaped like glands, with many duct-like branches. When individual tumor cells are isolated and used to grow artificial 3D cell clusters in the laboratory, referred to as organoids, the conventional approach produces only spherical like structures. These don't have the same morphology and properties as the tumor nodules in the body," says Aristeidis Papargyriou, the study's lead author. "Now we can generate organoids that greatly resemble the real, branched cell clusters found in the body. This lets us reproduce the complexity of pancreatic cancer in the laboratory for the first time."

More information:

- publication in Nature Biomedical Engineering:
https://nature.com/articles/s41551-024-01273-9

- TUM press information:
https://www.tum.de/en/news-and-events/all-news/press-releases/details/organoids-represent-the-complex-cell-landscape-of-pancreatic-cancer

Forschende bilden mit Organoiden, dreidimensionalen Minitumoren im Labor, erstmals die komplexen Strukturen und Eigenschaften von Bauchspeicheldrüsenkrebs nach.

27/03/2024

Translational Seminar in : We had the pleasure to welcome Elisa Espinet, PhD, University of Barcelona (UB) and Bellvitge Institute of Research in Biomedicine (IDIBELL), Spain, who gave a fantastic talk about epigenetics and microenvironment. A full auditorium of researchers and students listened to an inspiring new developments on biology!

We thank Elisa for sharing all the exciting data and we are already looking forward to next visit!

Save the date – our next seminar

- on 23.05.2024
- with Dr. med. Stephanie Frenz-Wießner, Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU Klinikum München

More information:
https://www.med2.mri.tum.de/en/seminar_series/index.php

TU München Helmholtz Juniors MGC Doctoral Candidates