Medizinische Klinik und Poliklinik II
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Akute und chronische Pankreatitis

AG Prof. Dr. Julia Mayerle / PD Dr. Georg Beyer

The role of stroma in chronic pancreatitis

Chronic pancreatitis is a progressive fibroinflammatory syndrome of the pancreas accompanied by a loss of endocrine and exocrine organ function, chronic pain and an increased risk for pancreatic cancer. Currently there is no effective treatment available to stop the self-perpetuating inflammation and organ dysfunction. Pancreatic stellate cells (PSCs) are pancreas specific mesenchymal cells, which are activated during chronic inflammation and mainly contribute to the fibrotic response. They also interact with inflammatory cells. The role of stellate cell activation and the attributed fibrosis for the progression of chronic pancreatitis, organ dysfunction and pain is not understood and experimental data on the inhibition of stellate cells is somewhat conflicting. We therefore aim to better understand the role of stellate cells and fibrosis for progression of chronic pancreatitis thus hoping to identify targets for specific treatments.

Prof. Dr. med. Julia Mayerle

Direktorin der Medizinischen Klinik und Poliklinik 2 und Arbeitsgruppenleiterin

  • Akute und chronische Pankreatitis
  • Entwicklung von diagnostischen Biomarkern für Pankreaserkrankungen
  • Zielgerichtete Therapien beim Pankreaskarzinom
  • Lipid-Metabolimus im Pankreaskarzinom

PD Dr. rer. biol. hum. Ivonne Regel

Laborleiterin der Forschungslabore der Medizinischen Klinik 2 und Projektleiterin

  • Epigenetische Veränderungen bei der Azinuszellreprogrammierung
  • Signalwegs-induzierte epigenetische Modifikationen
  • Inflammatorisches und metabolisches Priming von Azinuszellen
  • Tumor-Stroma Interaktion bei pankreatischen Vorläuferläsionen

PD Dr. med. Georg Beyer

Assistenzarzt und Projektleiter

  • Prognostische und prädiktive Marker für chronische Pankreatitis
  • Fibrotische Reaktion bei inflammatorischen Pankreaserkrankungen
  • Autoimmunpankreatitis

PD Dr. rer. med. Ujjwal Mukund Mahajan

PostDoc

  • Zielgerichtete Therapien beim Pankreaskarzinom
  • Lipid-Metabolimus im Pankreaskarzinom
  • Tumor-Stroma Interaktion im metastasierten Pankreaskarzinom
  • Mikrolithiasis und akute Pankreatitis

Ahmed Alnatsha, M.Sc.

PhD Doktorand

  • Lipid-Metabolimus im Pankreaskarzinom
  • Organoidkulturen aus dem Pankreaskarzinom

Lisa Fahr, M.Sc.

PhD Doktorandin

  • Epigenetische Veränderungen bei der Pankreaskarzinogenese
  • Signalwegs-induzierte epigenetische Modifikationen

Dr. Ahmad Mahmood, Pharm-D,MD

  • Gallstone induced Pancreatitis
  • Microlithiasis

Prince, M.Pharm.

PhD Doktorand

  • Fibrotische Reaktion bei inflammatorischen Pankreaserkrankungen

Nicole Schreiner, M.Sc.

PhD Doktorandin

  • Epigenetische Veränderungen bei der Azinuszellreprogrammierung
  • Inflammatorisches und metabolisches Priming von Azinuszellen

Quan Zhou, M.med.

PhD Doktorandin

  • Signalwegs-induzierte epigenetische Modifikationen
  • Inflammatorisches und metabolisches Priming von Azinuszellen

Dr. med. Elisabetta Goni

Fachärztin

  • Autoimmunpankreatitis
  • Biomarkern für Pankreaserkrankungen

Dr. med. Sarah Klauss

Assistenzärztin

Dr. med. univ. Elisabeth Orgler

Assistenzärztin

  • Autoimmunpankreatitis

Dr. med. Simon Sirtl

Assistenzarzt

  • Mikrolithiasis
  • akute Pankreatitis

Dr. med. Jakob Vielhauer

Assistenzarzt

Dr. med. Marlies Vornhülz

Assistenzärztin

  • Tumor-Stroma Interaktion bei pankreatischen Vorläuferläsionen

Veronika Hübner, cand. med.

Medizinische Doktorandin

  • Mitophagie im Pankreaskarzinom

Francesca Mendia, cand. med.

Medizinische Doktorandin

  • Zielgerichtete Therapien beim Pankreaskarzinom

Didem Saka, cand. med.

Assistenzärztin

  • Einfluss der Heterogenität von Krebs-Assoziierten Fibroblasten (CAFs) auf die Gestaltung der immunsuppressiven Tumormikroumgebung

Julia Wolff, cand. med.

Medizinische Doktorandin

  • Inflammatorisches und metabolisches Priming von Azinuszellen

Maria del Socorro Escobar Lopez

Technische Assistentin

Simon Gahr

Technischer Assistent

Alumni

Lisa Wurdak

Dr. med. Florian Scheufele

Dr. med. Michal Zorniak

Qi Li, cand. med.

Yonggan Yue, cand. med.

Andrea Hofmann, cand. med.

Julian Peterhansl, cand. med.

Regina Bocksberger, cand. med.

Svenja Pichlmeier, cand. med.

Hannah Lisiecki, cand. med.

Anna Kirmayr, cand. med.

Dr. rer. nat. Simone Benitz

Epigenetische Veränderungen bei der Pankreaskarzinogenese

AG Dr. Ivonne Regel

Epigenetic remodeling in carcinogenesis

The exocrine compartment of the pancreas contains mostly digestive enzyme producing acinar cells. Mouse model studies have shown that pancreatic acinar cells have regenerative properties and transform into tumor cells in the presence of oncogenic Kras. In both events, acinar cells undergo acinar-ductal metaplasia (ADM), which is accompanied by extensive transcriptional reprogramming. In own studies, we demonstrated that the reprogramming of acinar cells is mainly controlled by epigenetic mechanisms and changes in histone modifications. The accumulation of repressive histone modifications at acinar cell differentiation genes is a crucial factor pancreatic regeneration and carcinogenesis. In our projects, we investigate how oncogenic, inflammatory and metabolic cell stress affects the epigenetic signature of acinar cells and contributes to acinar cell reprogramming. Furthermore, we want to find out to what extent epigenetic signatures are responsible for a more aggressive tumor phenotype.

Inflammatory signaling in epithelial cells

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor disease. Despite intensive research, the causes of tumor initiation and aggressive progression are poorly understood. A strong fibroinflammatory response is a specific feature of PDAC and influences tumor aggressiveness. Our work has shown that the immune-modulatory Tlr3/Irf3/Irf7 pathway is not only active in immune cells but also in tumor cells. Genetic depletion of the Irf3/Irf7 transcription factors in a pancreatic tumor mouse model prevented pancreatic cancer development, whereas activation of the pathway promoted tumor aggressiveness. Our data provide evidence for a link to epigenetically regulated mechanisms.

Benitz S, Straub T, Mahajan UM, Mutter J, Czemmel S, Unruh T, Wingerath B, Deubler S, Fahr L, Cheng T, Nahnsen S, Bruns P, Kong B, Raulefs S, Ceyhan GO, Mayerle J, Steiger K, Esposito I, Kleeff J, Michalski CW, Regel I. (2019). "Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis." Gut. 2019 Nov;68(11):2007-2018.

Regel I, Raulefs S, Benitz S, Mihaljevic C, Rieder S, Leinenkugel G, Steiger K, Schlitter AM, Esposito I, Mayerle J, Kong B, Kleeff J, Michalski CW. (2019). "Loss of TLR3 and its downstream signaling accelerates acinar cell damage in the acute phase of pancreatitis." Pancreatology 19(1): 149-157.

Mahajan UM, Langhoff E, Goni E, Costello E, Greenhalf W, Halloran C, Ormanns S, Kruger S, Boeck S, Ribback S, Beyer G, Dombroswki F, Weiss FU, Neoptolemos JP, Werner J, D'Haese JG, Bazhin A, Peterhansl J, Pichlmeier S, Büchler MW, Kleeff J, Ganeh P, Sendler M, Palmer DH, Kohlmann T, Rad R, Regel I, Lerch MM, Mayerle J., Immune Cell and Stromal Signature Associated with Progression-free Survival of Patients with Resected Pancreatic Ductal Adenocarcinoma, Gastroenterology. 2018 Nov;155(5):1625-1639.e2. doi: 10.1053/j.gastro.2018.08.009.

Benitz, S.*, I. Regel*, T. Reinhard, A. Popp, I. Schaffer, S. Raulefs, B. Kong, I. Esposito, C.W. Michalski, and J. Kleeff, Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells., Oncotarget, 2016. 7(10): p. 11424-33., *equally contributed

Hausmann S, Regel I, Steiger K, Wagner N, Thorwirth M, Schlitter AM, Esposito I, Michalski CW, Friess H, Kleeff J, Erkan M., Loss of Periostin Results in Impaired Regeneration and Pancreatic Atrophy after Cerulein-Induced Pancreatitis., Am J Pathol, 2016. 186(1): p. 24-31.

  1. Wilhelm Sander-Stiftung, Irf3/Irf7-mediated epigenetic gene regulation in pancreatic carcinogenesis. 2019.083.1 (2020 – 2021)
  2. DFG, Determining the cellular decision of pancreatic acinar cells undergoing a transient regeneration program or persistent tumorigenesis. RE 3754/3-1 (2021 – 2024)

PD Dr. rer. biol. hum. Ivonne Regel

Laborleiterin der Forschungslabore der Medizinischen Klinik 2 und Projektleiterin

  • Epigenetische Veränderungen bei der Azinuszellreprogrammierung
  • Signalwegs-induzierte epigenetische Modifikationen
  • Inflammatorisches und metabolisches Priming von Azinuszellen
  • Tumor-Stroma Interaktion bei pankreatischen Vorläuferläsionen

Lisa Fahr, M.Sc.

PhD Doktorandin

  • Epigenetische Veränderungen bei der Pankreaskarzinogenese
  • Signalwegs-induzierte epigenetische Modifikationen

Nicole Schreiner, M.Sc.

PhD Doktorandin

  • Epigenetische Veränderungen bei der Azinuszellreprogrammierung
  • Inflammatorisches und metabolisches Priming von Azinuszellen

Quan Zhou, M.med.

PhD Doktorandin

  • Signalwegs-induzierte epigenetische Modifikationen
  • Inflammatorisches und metabolisches Priming von Azinuszellen

Dr. med. Elisabetta Goni

Fachärztin

  • Autoimmunpankreatitis
  • Biomarkern für Pankreaserkrankungen

Dr. med. Sarah Klauss

Assistenzärztin

Dr. med. univ. Elisabeth Orgler

Assistenzärztin

  • Autoimmunpankreatitis

Dr. med. Marlies Vornhülz

Assistenzärztin

  • Tumor-Stroma Interaktion bei pankreatischen Vorläuferläsionen

Veronika Hübner, cand. med.

Medizinische Doktorandin

  • Mitophagie im Pankreaskarzinom

Julia Wolff, cand. med.

Medizinische Doktorandin

  • Inflammatorisches und metabolisches Priming von Azinuszellen

Maria del Socorro Escobar Lopez

Technische Assistentin

Simon Gahr

Technischer Assistent

Alumni

  • Lisa Wurdak
  • Dr. med. Florian Scheufele
  • Svenja Pichlmeier, cand. med.
  • Hannah Lisiecki, cand. med.
  • Anna Kirmayr, cand. med.
  • Dr. rer. nat. Simone Benitz

Targeted delivery approaches in pancreatic cancer

AG PD Dr. Ujjwal Mukund Mahajan

Aptamer-based targeted therapy for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumor diseases with an enormously poor prognosis due to limited standard chemotherapeutic options. One possible explanation for the poor response to chemotherapies is an insufficient and non-specific transport to the tumor. In our projects, we develop aptamers (single-stranded, three-dimensional oligonucleotides) that can bind with a high specificity and affinity to molecular surface proteins of tumor cells or other cells. Notably, we can generate aptamers endowed with therapeutic and diagnostic properties (theranostic). In order to identify relevant tumor targets, we investigate metabolic changes in tumor cells as well as the tumor stroma, which accounts for a large proportion of the tumor mass in PDAC. Inflammatory and fibrotic processes are significantly involved in tumor progression and therapy response, and we are analyzing the composition of the compartments and their functional relevance.

The role of sphingolipids in pancreatic cancer

Sphingolipids are bioactive molecules that have key roles in the regulation of cancer cell signaling to control tumor suppression or survival. Ceramide is a central metabolite in sphingolipid metabolism pathways and plays a key role in a variety of cellular responses, including regulation of cell growth, viability, differentiation, and senescence. Our aim is to find out how the sphingolipid metabolic pathway influences various tumor processes, such as general tumor growth, metastasis and the response to radio / chemotherapy. Moreover, we are working on finding new diagnostic and prognostic marker for PDAC using Metabolome analysis.

U. M. Mahajan, B. Oehrle, S. Sirtl, A. Alnatsha, E. Goni, I. Regel, G. Beyer, M. Vornhülz,Vielhauer, A.Chromik, M.Bahra, F.Klein, W.Uhl, T.Fahlbusch, M.Distler, J.Weitz, R.Gutzmann, C. Pilarsky, F. U. Weiss, G. Adam, J. Neoptolemos, H. Kalthoff, R. Rad, N Christiansen, B. Bethan, B. Kamlage, M. M. Lerch, J. Mayerle. Independent validation and assay standardization of improved metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis, Gastroenterology (2022).

U. M. Mahajan*, Q. Li*, A. Alnatsha, J. Maas, M. Orth, S. H. Maier, J. Peterhansl, I. Regel, M. Sendler, P.R.Wagh, N.Mishra, Y.Xue, P.Allawadhi, G.Beyer, J.-P.Kühn, T.Marshall, B.Appel, F. Lämmerhirt, C. Belka, S. Müller, F.-U. Weiss, K. Lauber, M. M. Lerch, J. Mayerle, Tumor-Specific Delivery of 5-Fluorouracil-Incorporated Epidermal Growth Factor Receptor-Targeted Aptamers as an Efficient Treatment in Pancreatic Ductal Adenocarcinoma Models, Gastroenterology (2021).

U. M. Mahajan, E. Langhoff, E. Goni, E. Costello, W. Greenhalf, C. Halloran, S. Ormanns, S. Kruger, S. Boeck, S. Ribback, G. Beyer, F. Dombroswki, F.-U. Weiss, J. P. Neoptolemos, J. Werner, J. G. D’Haese, A. Bazhin, J. Peterhansl, S. Pichlmeier, M. W. Büchler, J. Kleeff, P. Ganeh, M. Sendler, D. H. Palmer, T. Kohlmann, R. Rad, I. Regel, M. M. Lerch, J. Mayerle, Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma, Gastroenterology (2018).

G. Beyer*, U. M. Mahajan*, C. Budde*, T. J. Bulla, T. Kohlmann, L. Kuhlmann, K. Schütte, A. A. Aghdassi, E. Weber, F. U. Weiss, A. M. Drewes, S. S. Olesen, M. M. Lerch, J. Mayerle, Development and Validation of a Chronic Pancreatitis Prognosis Score in 2 Independent Cohorts, Gastroenterology (2017).

U. M. Mahajan, S. Teller, M. Sendler, R. Palankar, C. van den Brandt, T. Schwaiger, J.-P. Kühn, S. Ribback, G. Glöckl, M. Evert, W. Weitschies, N. Hosten, F. Dombrowski, M. Delcea, F.-U. Weiss, M. M. Lerch, J. Mayerle, Tumour-specific delivery of siRNA-coupled superparamagnetic iron oxide nanoparticles, targeted against PLK1, stops progression of pancreatic cancer, Gut (2016).

T. Patino, U. M. Mahajan, R. Palankar, N. Medvedev, J. Walowski, M. Münzenberg, J. Mayerle, M. Delcea, Multifunctional gold nanorods for selective plasmonic photothermal therapy in pancreatic cancer cells using ultra-short pulse near-infrared laser irradiation, Nanoscale (2015). 

  1. BMBF, Plasma-Metabolom Multimarker-Test für die Diagnose des Pankreaskarzinoms in Risikogruppen (META-PAC), 01EK1511A, Mayerle (2015 – 2022)
  2. DFG, Biologische Rolle von Sphingolipiden beim Pankreaskarzinom, SFB1321 P14 – 329628492, Mayerle (2018 – 2022)
  3. Deutsche Krebshilfe, Clinical validation of predictive signatures in prospective collection of biopsy material of metastasis of patients with stage IV PDAC, 70113834, Mayerle (2021 – 2024)

PD Dr. rer. med. Ujjwal Mukund Mahajan

PostDoc

  • Zielgerichtete Therapien beim Pankreaskarzinom
  • Lipid-Metabolimus im Pankreaskarzinom
  • Tumor-Stroma Interaktion im metastasierten Pankreaskarzinom
  • Mikrolithiasis und akute Pankreatitis

Ahmed Alnatsha, M.Sc.

PhD Doktorand

  • Lipid-Metabolimus im Pankreaskarzinom
  • Organoidkulturen aus dem Pankreaskarzinom

Prince, M.Pharm.

PhD Doktorand

  • Fibrotische Reaktion bei inflammatorischen Pankreaserkrankungen

Dr. med. Simon Sirtl

Assistenzarzt

  • Mikrolithiasis
  • akute Pankreatitis

Dr. med. Jakob Vielhauer

Assistenzarzt

Dr. med. Marlies Vornhülz

Assistenzärztin

  • Tumor-Stroma Interaktion bei pankreatischen Vorläuferläsionen

Francesca Mendia, cand. med.

Medizinische Doktorandin

  • Zielgerichtete Therapien beim Pankreaskarzinom

Didem Saka, cand. med.

Assistenzärztin

  • Einfluss der Heterogenität von Krebs-Assoziierten Fibroblasten (CAFs) auf die Gestaltung der immunsuppressiven Tumormikroumgebung

Maria del Socorro Escobar Lopez

Technische Assistentin

Simon Gahr

Technischer Assistent

Alumni

  • Dr. med. Michal Zorniak
  • Qi Li, cand. med.
  • Yonggan Yue, cand. med.
  • Andrea Hofmann, cand. med.
  • Julian Peterhansl, cand. med.
  • Regina Bocksberger, cand. med.