The RTG is divided into three main research areas, under which the individual research projects are organized (A: In vivo modeling, B: In vitro modeling, C: Target characterization). There is close collaboration between the researchers as well as with national and international research groups. The individual projects are presented below.
Prinicipal investigators: Prof. Jonas Rosendahl, Dr. Helmut Laumen
PhD student: Tanvi Inamdar
Both chronic pancreatitis (CP) and obesity are well-known risk factors for pancreatic cancer. In previous studies, we found loss-of-function mutations in CPA1, encoding the digestive enzyme carboxypeptidase A1, both in sporadic early onset and in hereditary CP. A recent study using a genetic mouse model showed that the p.N256K mutation of CPA1 (Cpa1N256K) is sufficient to cause CP and acinar-to-ductal-metaplasia (ADM), most likely by ER stress-related mechanisms. Moreover, numerous studies showed an impact of obesity on pancreatic cancer development in well-established mouse models such as KC (KrasG12D/wt;p48Cre+/-).
In this project, we will assess the impact of genetically driven chronic inflammation on early pancreatic carcinogenesis by combining the two mouse models Cpa1N256Kand KC. Additionally, we aim to further challenge control, Cpa1N256K, KC and KC-Cpa1N256K mice by feeding a high fat diet to compare the impact of obesity and genetically driven CP, and assess the combined impact of both challenges on early pancreatic cancer development. A broad range of histological, immunological and molecular biological readouts will provide us with differentiated insights into carcinogenesis in the pancreas and the underlying signalling pathways of this process.
Principal investigator: Prof. Martin Gericke
PhD student: Anne-Kristin Fritsche
Obesity is associated with chronic inflammation in several organs including the pancreas. Both obesity and chronic pancreatitis are well-established risk factors for pancreatic cancer. Interestingly, intermittent fasting has been shown to reduce the incidence of obesity-associated mammary carcinogenesis in mouse models.
Whether intermittent fasting also reduces obesity-associated carcinogenesis in the pancreas is still elusive. Furthermore, the underlying molecular mechanisms remain to be deciphered. This project is dedicated to these tasks. We place particular emphasis on the role of M2 macrophages as cellular mediators of inflammation and carcinogenesis in the pancreas as well as interleukin-4 pathways.
Principal investigator: Prof. Patrick Michl
PhD student: vacant
Emerging evidence suggests that intestinal microbiota influence pancreatic carcinogenesis and therapeutic response: Bacterial ablation by oral antibiotics was shown to greatly delay tumor progression, whereas transfer of bacteria from PDAC-bearing mice reversed this protection. Interestingly, bacterial ablation was associated with immunological reprogramming of the tumor microenvironment (including reduction of myeloid-derived suppressor cells and increased differentiation and activation rates of M1 macrophages and T cells). In addition, tumors were more susceptible to immunotherapy (checkpoint inhibition) due to upregulation of the PD-1 receptor.
These findings indicate a significant role and therapeutic potential of microbiota in the development of pancreatic cancer. However, the precise interplay between different triggers of inflammation, intestinal as well as intrapancreatic microbiota and the development of early (pre)invasive neoplasia remains poorly understood. This project therefore aims to unravel the influence of intestinal microbiota on inflammation-induced early pancreatic carcinogenesis and the interaction between inflammatory cues and microbiota.
Principal investigators: Prof. Sebastian Krug, Prof. Sonja Keßler
PhD student: Atul Verma
Tumor-associated macrophages (TAM) represent an important constituent of the inflammatory tumor microenvironment which have been implicated as crucial mediators of tumor progression, but can be found already in the stroma surrounding preneoplastic PanIN lesions. Targeting TAMs represents a promising avenue to overcome therapy resistance mediated by the highly immune-evasive stroma of pancreatic cancer.
In contrast to the well-studied role of TAMs in established tumors, their impact during early inflammation-driven carcinogenesis is largely unknown. In addition, alterations in the lipid metabolism have been shown to play an important role in determining the phenotype of myeloid cells. However, the impact of myeloid cells on the lipid metabolism of early pancreatic precursor cells in the context of chronic inflammation remains to be elucidated. In this project, we aim to decipher the contribution of myeloid cells to inflammation-induced early carcinogenesis and the potential for therapeutic modulation.
Principal investigators: Prof. Heike Kielstein, PD Ivonne Bazwinsky-Wutschke
PhD student: Elise Arlt
Natural killer (NK) cells represent a subset of innate lymphoid cells, playing a pivotal role in host immunity against various malignancies. Several reports describe multiple defects of NK cells in PDAC patients. It has also been shown that progression of PDAC is closely associated with dysfunctional circulating NK cells. Our own studies emphasized that functionality and phenotype of NK cells are impaired during obesity, a state of chronic low-grade inflammation, leading to a reduced immune surveillance in various cancer models. In line with these findings, a significant decrease in NK cell numbers and function has been demonstrated in obese KC mice.
In this project we will unravel the impact of NK cells during early inflammation-induced pancreatic carcinogenesis by deciphering effects on both pre-invasive cells and other components of the tumor microenvironment including the endocrine compartment. In addition, we will explore pharmacological options of NK cell modulation during early carcinogenesis. To this end, we will utilize a broad range of histological, molecular biological and immunological research tools.
Principal investigators: Prof. Jörg Kleeff, Dr. Markus Glaß
PhD student: Nupur Ohri
Several studies have shown that in addition to oncogenic K-Ras, molecular components including transforming growth factor-α (TGF-α), epidermal growth factor receptor (EGFR), PI3K signaling, and others are important in driving ADM formation, and that the Raf/MEK/ERK pathway is essential for early ADM/PanIN formation. Recent findings suggest that activation of these signaling pathways in epithelial cells during tumor initiation and progression is promoted by paracrine factors from stromal fibroblasts including pancreatic stellate cells (PSC).
However, the exact role of the stromal reaction and particularly PSCs observed around early pre-neoplastic lesions is currently not known. In this project, we aim to identify and characterize the impact of PSCs during inflammation-driven early pancreatic carcinogenesis. To this end, we will analyze the three different models of inflammation-driven pancreatic carcinogenesis and functionally characterize genes of interest both in vitro and in vivo.
Principal investigator: apl. Prof. Lutz Müller
PhD student: Tina Seidel
The pancreatic stroma comprising heterogenous cell types including PSCs, fibroblasts and immune cells contributes to PDAC carcinogenesis by providing immunomodulating cytokines like IL-6 as well as extracellular matrix (ECM). While distinct roles for various stromal cells have been demonstrated in fully transformed PDAC, the specific role of defined stroma cell subpopulations during pancreatic carcinogenesis remains elusive.
Recent studies suggest that subpopulations of pancreatic stromal cells share characteristics with mesenchymal stromal cells (MSC). We and others have shown that MSCs comprise a rare but ubiquitous cell type which harbors immunomodulatory capacity and can support malignant growth. In this project, we aim to characterize native pancreatic MSCs during stages of pancreatic carcinogenesis and to define MSC-specific immunomodulatory effects contributing to inflammation-driven PDAC development.
Principal investigator: Monika Hämmerle, M.D., Ph.D.
PhD student: Juliane Blühmke
Principal investigator: Nadine Bley, Ph.D.
PhD student: Hend Elrewany
Principal investigators: Andrea Sinz, Ph.D.; Stefanie Göllner, Ph.D.
PhD student: Florian Wolfgang Otto
Principal investigator: Stefan Hüttelmaier, Ph.D.
PhD student: Khursheed Ul Islam Mir
Principal investigator: Tony Gutschner, Ph.D.
PhD student: Pit Preckwinkel
Principal investigator: Michael Böttcher, Ph.D.
PhD student: Erik Haußner