Projects

Prinicipal investigators: Prof. Jonas Rosendahl, Dr. Helmut Laumen

1st generation (April 2022 - March 2025):

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 (Cpa1^N256K) 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 (Kras^G12D/wt;p48^Cre+/-).

In this project, we will assess the impact of genetically driven chronic inflammation on early pancreatic carcinogenesis by combining the two mouse models Cpa1^N256K and KC. Additionally, we aim to further challenge control, Cpa1^N256K, KC and KC-Cpa1^N256K 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.

2nd generation (April 2025 - March 2028):

PhD student: open position

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 (Cpa1^N256K) is sufficient to cause CP and acinar-to-ductal-metaplasia (ADM). Moreover, numerous studies showed an impact of obesity on pancreatic cancer development in well-established mouse models such as KC (Kras^G12D/wt;p48^Cre+/-).

To assess the impact of genetically driven pancreatitis on the development of pancreatic cancer we combined the two mouse models KC and Cpa1^N256K to the KC-Cpa1 genotype. Pancreata of KC-Cpa1 as well as Cpa1, KC and Cre mice were analysed histologically at various early and late time points to investigate remodeling, fibrosis and formation of pancreatic intraepithelial neoplasia (PanIN) lesions. Additionally both, bulk RNAseq and single cell sequencing (sc-RNAseq) of KC-Cpa1, Cpa1, KC and Cre mice pancreata was performed at different early time points. In addition, primary mouse acini were isolated from mouse pancreas and embedded in collagen to model acinar-to-ductal metaplasia (ADM). In KC-Cpa1 mice we found significantly increased remodeling, fibrosis and increased number of PanIN lesions as compared to control mice. scRNAseq provided novel insight into the cellular landscape of the novel KC-Cpa1 model by giving a deep insight into the transcriptional program of acinar metaplastic cells. Finally, the ex vivo model of ADM showed that acini isolated from KC-Cpa1 mice underwent transdifferentiation spontaneously, which was notably faster compared to the control mice.

In this project, we will further uncover the precise molecular pathways responsible for the phenotype observed in KC-Cpa1 mice by combining in vitro, ex vivo and in vivo techniques based on our previous results and using further genetic models. Using both, an acinar cell line and an established 3D culture of primary acini, enable us to gain deeper insight into molecular pathways inferred from our bulk and scRNAseq in KC-Cpa1 mice. Going beyond these in vitro / ex vivo studies, we aim to perform further mouse studies using a mouse model (Ptf1aCreERT) in which the cancer mutation Kras^G12D can be induced by tamoxifen. In humans, the combined effect of multiple risk factors may finally contribute to development of cancer. Here we will apply high-fat diet feeding to model the risk factor obesity combined with the human pancreatitis mutation Cpa1^N256K. In obese KC-Cpa1 mice, we can induce the Kras^G12D mutation, enabling us to model the human situation. Additionally to the scRNAseq data generated so far, we aim to perform spatial scRNAseq experiments to gain deeper insight into the cellular and molecular mechanisms. 

In summary, based on our previous results from the KC-Cpa1 mice, this project will further dissect the impact of a novel spontaneous genetic mouse model for inflammation-induced pancreatic carcinogenesis and its interplay with obesity as further clinically relevant pancreatic cancer risk factor. Our data may provide novel avenues for prevention strategies in high-risk individuals due to obesity and hereditary predispositions.

Principal investigator: Prof. Martin Gericke

1st generation (April 2022 - March 2025):

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.

2nd generation (April 2025 - March 2028):

PhD student: open position

One of the most aggressive cancers is pancreatic ductal adenocarcinoma (PDAC), which is often associated with chronic pancreatitis. Obesity is a known risk factor for several diseases and cancers, including PDAC, and is associated with a state of chronic inflammation in several tissues. However, the underlying mechanisms by which obesity promotes pancreatic carcinogenesis are poorly understood. Therefore, we investigated whether obesity affects the immune profile of the pancreas in mice. Genetically induced obesity and high fat diet (HFD)-induced obesity models were studied and immune cell populations within the pancreas were analyzed. Interestingly, significant changes were observed in myeloid-derived suppressor cells (MDSCs), tissue-resident macrophages (PanMs) and dendritic cells (DCs). With regard to T cells, neither T helper, cytotoxic nor regulatory T cells showed differences in abundance. 

Most interestingly, we observed a consistent downregulation of CD301 on the cell surface of most myeloid immune cells in different obesity models. As CD301 is a known receptor for carbohydrate-rich tumor antigens, we will focus on its obesity-associated regulation and effects during obesity-associated tumorigenesis in the next funding period. Using live imaging and multi-omics of immune-cancer cell interactions, the importance of CD301 for immune evasion of PDAC cells will be investigated.

Principal investigator: Prof. Patrick Michl

1st generation (April 2022 - March 2025):

PhD student: Miquel Tibau Baltrons

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.

2nd generation (April 2025 - March 2028):

PhD student: Miquel Tibau Baltrons

Principal investigators: Prof. Sebastian Krug, Prof. Sonja Keßler

1st generation (April 2022 - March 2025):

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.

2nd generation (April 2025 - March 2028):

PhD student: open position

Tumor-associated macrophages (TAM) have been implicated as crucial mediators of tumor progression. Targeting TAMs represents a promising avenue to overcome therapy resistance mediated by the highly immune-evasive stroma of pancreatic cancer. Previously, we showed that TAM depletion by liposomal clodronate significantly delays tumor progression in two genetic mouse models of pancreatic tumorigenesis. In addition, we demonstrated that TAMs exert a high plasticity during tumor progression. In contrast to their well-studied role in established tumors, the impact of TAMs during early inflammation-driven carcinogenesis is largely unknown. Our initial work indicates distinct transcriptomic alterations in pre-neoplastic KC cells upon co-culture with differently polarized myeloid cell populations. 

During the first period of the RTG we established a co-culture model to characterize interactions between macrophages and tumor cells, researched the step-wise contribution of immune cell populations in the genetic engineered KC/KPC models and obtained descriptive sequencing data from tumor cells and macrophages in a well-characterized human PDAC cohort. 

The following project aims to functionally characterize the results of the mouse/human data and mechanistically implement approaches to target subpopulations of macrophages and specific signalling pathways.

For this purpose, we will

1) Comprehensively characterize the metabolic and lipiodomic profile of the co-culture experiment (alterations in preinvasive KC cells upon co-culture with differently polarized primary myeloid cell populations). Targets suitable for early diagnosis or therapeutic intervention will be validated individually. 

2) Investigation of the mechanism of the potential targets in TAMs and validation of the potential targets by e.g. pharmacological inhibition

3) Characterize the impact of myeloid subpopulations in the different molecular subtypes of pancreatic adenocarcinomas with the goal to provide rationales for myeloid targeting

Principal investigators: Prof. Heike Kielstein, PD Ivonne Bazwinsky-Wutschke

1st generation (April 2022 - March 2025):

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.

2nd generation (April 2025 - March 2028):

PhD student: open position

The main topic of the B2 project is to investigate the influence of Natural Killer (NK) cells during early inflammation-induced pancreatic carcinogenesis by deciphering the interaction of NK cells with both pre-invasive cells and other components of the tumor microenvironment including the endocrine compartment. The KC mouse model is used to investigate an early, precancerous stage of pancreatic ductal adeno carcinoma (PDAC). Primary NK cells will be analyzed concerning their numbers, distribution and function in various compartments (pancreas, blood, spleen). Different time points in tumor progression will be examined and blood samples will be analyzed in parallel to reveal changes in peripheral NK cells. In addition to in vivo studies, in vitro studies will be performed. For this purpose, different PDAC cell lines, endocrine cell lines, as well as NK cell lines will be used to perform co-cultures, molecular and functional assays. The progression of PDAC, as well as the incidences, prognosis and therapy outcome are strongly sex dependent. Therefore, in the framework of this project great focus is placed on the impact of sex. For this purpose, NK cell functions and the tumor progression will be compared between males and females.

Principal investigators: Prof. Jörg Kleeff, Dr. Markus Glaß

1st generation (April 2022 - March 2025):

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.

2nd generation (April 2025 - March 2028):

PhD student: open position

In early pancreatic carcinogenesis, pro-inflammatory signals not only activate fibroblasts and induce extracellular matrix (ECM) production but also reprogram fibroblasts into tumor-promoting CAF subtypes. These CAF subtypes significantly contribute to the growth of premalignant cells and the establishment of an immunosuppressive tumor microenvironment, partly by recruiting immunosuppressive immune cells. Initial analyses identified Angptl4 as a gene consistently upregulated in CAFs during early carcinogenesis, with higher expression in antigen-presenting CAFs (apCAFs) compared to inflammatory CAFs (iCAFs). However, the role of Angptl4 and other factors in CAF plasticity and their differentiation into tumor-promoting subtypes remains unclear.

This project aims to identify key genes in CAFs and analyze their functional roles to develop stratified targeting strategies. Using genetic modifications via CRISPR, 3D organoid models, and single-cell RNA sequencing, we will study CAF trans-differentiation and their interactions with PanIN pancreatic cells. Finally, targeted inhibitors will be tested to evaluate whether selective modulation of CAF subtypes can suppress tumor growth and progression, offering potential for therapeutic interventions.

Principal investigator: apl. Prof. Lutz Müller

1st generation (April 2022 - March 2025):

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.

2nd generation (April 2025 - March 2028):

PhD student: open position

The biology of pancreatic ductal adenocarcinoma (PDAC) is characterized by a strong impact of carcinoma-associated fibroblasts (CAF). Mesenchymal stroma cells (MSC) represent a rare yet ubiquitous, immature and immunomodulatory stromal cell population. Data from the first project phase demonstrate differential presence, transcriptomic signature and functional characteristics of MSC-like cells at different stages of early PDAC. Further work of our group shows that MSC undergo differentiation to CAF under control of TGF-β / MRTF-signalling.

We hypothesize that in inflammation-related PDAC pancreatic MSC-like cells undergo differentiation towards CAF through signals from inflammatory microenvironment and that this differentiation is controlled by TGF-β / MRTF. The project aims to identify the signals driving this differentiation and its effect on carcinogenesis. 

Specifically we will model interaction of MSC / stroma cells with immune and (pre-)cancerous epithelial cells (murine KC-/KC-Cpa1-models; human PDAC cell lines) using different in vitro and in vivo systems (3D co-culture, organoids, allo-/xenografts). In these systems we will characterize interaction, differential gene expression (including single cell RNAseq) and cytokine release driving MSC / stroma cell differentiation upon inflammatory signaling. By applying CRISPR/Cas-screening we will define relevant regulators of CAF-differentiation. The role of identified target genes will be validated by loss- / gain-of-function approaches and a transgenic mice model. Finally, we will validate the relevance of the identified signalling and differentiation in patient biomaterial of (pancreatitis, PanIn-samples) by scRNAseq. 

The project will add significantly to a better understanding of PDAC carcinogenesis and define new targets for therapeutic interventions. It will be carried out in close collaboration with the other groups of the research consortium as well as core facilities at the UMH / MLU. 

Principal investigator: Monika Hämmerle, M.D., Ph.D.

1st generation (April 2022 - March 2025):

PhD student: Juliane Blümke

2nd generation (April 2025 - March 2028):

PhD student: open position

Thrombocytosis is a common feature in patients with solid malignancies, especially patients with gastrointestinal and gynecological cancers (Levin and Conley, 1964). Therefore, platelet counts were suggested to serve as biomarkers of cancer (Bailey et al., 2016). Interestingly, pancreatic cancer patients have a high risk of developing severe thromboembolic complications, and vice versa, there is a six-fold higher relative risk for the subsequent diagnosis of an occult pancreatic carcinoma after the occurrence of a thromboembolic event (Iodice et al., 2008). We have shown before, that platelets are not merely bystanders in the circulation but rather active players in several steps of tumorigenesis (Haemmerle et al., 2018). Platelets significantly increase primary tumor growth (Haemmerle et al., 2016), anoikis resistance of circulating tumor cells and metastasis formation (Haemmerle et al., 2017; Ernesti et al., 2024) and contribute to therapy resistance (Haemmerle et al., 2016; Bottsford-Miller et al., 2015). Additionally, platelets secrete a variety of growth factors, cytokines and chemokines and can thereby affect the function as well as infiltration of immune cells into tissues. Particularly, platelets are a rich source of TGFβ containing 40 to 100 times more TGFβ than other cells and release this immunomodulatory cytokine rapidly after platelet activation (Assoian et al., 1983; Ahamed et al., 2008). Inhibition of platelet-derived TGFβ reduced proliferation and IFN-γ production of T-cells in vitro and enhanced efficacy of adoptive T-cell transfer in vivo (Rachidi et al., 2017). In addition, TGFβ can regulate macrophage polarization towards a M2-phenotype, which is suggested to support tumor growth (Gratchev, 2017). 

In this project, we will analyze the impact of platelets on immune cell infiltration and function with a specific focus on macrophages using co-culture experiments, flow cytometry as well as molecular biology techniques. Furthermore, we will analyze the quantitative and qualitative composition of the pancreatic immune microenvironment as a function of blood platelet counts as well as platelet-specific TGFβ using multispectral imaging in both cancer as well as pancreatitis in vivo and ex vivo models.

Principal investigator: Nadine Bley, Ph.D.

1st generation (April 2022 - March 2025):

PhD student: Hend Elrewany

2nd generation (April 2025 - March 2028):

PhD student: open position

In pancreatic ductal adenocarcinoma (PDAC), the receptor tyrosine kinase c-Met plays a critical role in tumor progression and metastasis. Upon binding with its ligand, hepatocyte growth factor (HGF), c-Met activates signaling cascades that drive cancer cell proliferation, survival, invasion, and angiogenesis. Overexpression and abnormal activation of c-Met are observed in PDAC, associated with aggressive tumor behavior, poor prognosis, and resistance to therapies. Recent findings suggest that c-Met also facilitates immune evasion in conjunction with the RNA-binding protein IGF2BP2, though the underlying mechanisms remain unclear. This project aims to: (i) identify how c-Met and IGF2BP2 expression is upregulated during PDAC development; (ii) elucidate how c-Met and IGF2BP2 repress T cell activation and impair T cell-mediated tumor cell killing; and (iii) assess whether c-Met and/or IGF2BP2 inhibitors can enhance immune response and potentially synergize with immune checkpoint therapies.

Principal investigators: Andrea Sinz, Ph.D.; Stefanie Göllner, Ph.D.

1st generation (April 2022 - March 2025):

PhD student: Florian Wolfgang Otto

2nd generation (April 2025 - March 2028):

PhD student: Florian Wolfgang Otto

Principal investigator: Stefan Hüttelmaier, Ph.D.

1st generation (April 2022 - March 2025):

PhD student: Khursheed Ul Islam Mir

2nd generation (April 2025 - March 2028):

PhD student: open position

The more than 1500 RNA binding proteins (RBPs) expressed in humans are key regulators of gene expression in malignancies, including pancreatic cancer (PDAC). Key examples of pro-oncogenic RBPs with therapeutic target potential and validated oncogenic roles in pancreatic cancer are IGF2BPs (IGF2 mRNA binding proteins). Studies in the first funding period of this RTG confirmed that IGF2BPs play essential roles in the early and late progression of PDAC. In continuation, project C2 will join forces with project B6 to decipher roles of IGF2BP family members in PDAC initiation (IGF2BP2), metabolic reprogramming and hypoxia responses (IGF2BP3) to exceeding proliferation, invasion and metastasis (IGF2BP1) in KRAS-driven PDAC. The proposed investigations will involve cellular analyses in established 3D cell models next to organoids derived from murine PDAC models as well as transgenic mice allowing the conditional transgene expression of all three human IGF2BPs. Aiming to transfer insights from murine to human, C2 will implement investigations on human PDAC organoids by perturbing studies implementing CRISPR technologies and small molecule inhibitors of IGF2BPs. 

Principal investigator: Tony Gutschner, Ph.D.

1st generation (April 2022 - March 2025):

PhD student: Pit Preckwinkel

2nd generation (April 2025 - March 2028):

PhD student: open position

The transforming growth factor-ß (TGF-ß) signaling pathway regulates several cellular functions, including cell growth, differentiation, adhesion, migration and cell death in a context-dependent and cell type-specific manner. In early-stage pancreatic cancer, TGF-β exhibits potent growth inhibitory effects by promoting apoptosis and inhibiting the cell cycle. Importantly, although TGF-β signaling can have potent tumor-suppressive effects in epithelial cells, it also accelerates pancreatic tumorigenesis by enhancing epithelial-to-mesenchymal transition (EMT), fibrosis, and the evasion of the cytotoxic immune surveillance program. Several research projects are currently ongoing to understand the duality of the TGF-ß pathway and we, together with our colleagues of the RTG 2751, have recently identified novel regulators of this pathway (Dorn et al., 2020; Wedler et al., 2024; Rosemann et al., 2024). In this project, we will study the role of non-coding RNAs (ncRNAs) as targets and downstream mediators of TGF-ß signaling effects. We will initially focus on the epithelial cell compartment and map the TGF-ß-regulated transcriptome of cells. Differentially regulated ncRNAs will be investigated further and their contribution to TGF-ß signaling outcomes will be characterized at the molecular level. Overall, our study aims to broaden our understanding of the underlying mechanisms mediating the pleiotropic roles of TGF-ß in pancreatic cancer.

Principal investigator: Michael Böttcher, Ph.D.

1st generation (April 2022 - March 2025):

PhD student: Erik Haußner

2nd generation (April 2025 - March 2028):

PhD student: open position

Project C4 aims to elucidate key genetic regulators of the NF-κB signaling pathway in the context of pancreatic carcinogenesis through comprehensive CRISPR-Cas9 loss-of-function screens. Given the crucial role of NF-κB in inflammation, tumor initiation and progression, understanding its regulatory network could reveal novel therapeutic targets. Using a genome-wide CRISPR library, we will systematically disrupt genes in pancreatic cancer cell models and assess changes in NF-κB pathway activity via reporter assays and downstream target gene expression. Hits from the screen will undergo secondary validation and mechanistic studies to confirm their role in NF-κB modulation. By identifying novel modulators of this pathway, the project aims to provide insights into the molecular drivers of pancreatic cancer and uncover potential targets for pharmacological intervention. Ultimately, these findings could contribute to the development of NF-κB-pathway-targeted therapies, offering new avenues to improve outcomes for patients with this highly aggressive cancer type.