Projekte

Projektleitung: Prof. Dr. Jonas Rosendahl, Dr. Helmut Laumen

1. Generation (April 2022 - März 2025):

PhD-Studentin: Tanvi Inamdar

Sowohl chronische Pankreatitis (CP) als auch Fettleibigkeit sind bekannte Risikofaktoren für Bauchspeicheldrüsenkrebs. In früheren Studien fanden wir Funktionsverlust-Mutationen im CPA1-Gen, welches für das Verdauungsenzym Carboxypeptidase A1 kodiert, sowohl bei sporadisch auftretender frühzeitiger als auch bei erblicher CP. Eine kürzlich durchgeführte Studie mit einem genetischen Mausmodell zeigte, dass die p.N256K-Mutation in CPA1 (Cpa1^N256K) ausreicht, um eine CP und Azinär-Duktale-Metaplasie (ADM) zu verursachen. Dies wahrscheinlich durch ER-Stress-bezogene Mechanismen. Darüber hinaus haben zahlreiche Studien gezeigt, dass Adipositas die Entwicklung von Bauchspeicheldrüsenkrebs in etablierten Mausmodellen wie KC (Kras^G12D/wt;p48^Cre+/-) beeinflusst.

In diesem Projekt werden wir die Auswirkungen einer genetisch bedingten chronischen Entzündung auf die frühe Pankreaskarzinogenese untersuchen, indem wir die beiden Mausmodelle Cpa1^N256K und KC kombinieren. Zusätzlich wollen wir Kontroll-, Cpa1^N256K-, KC- und KC-Cpa1^N256K-Mäuse mit einer fettreichen Diät füttern, um die Auswirkungen von Adipositas und genetisch bedingter CP zu vergleichen, sowie die kombinierte Auswirkung auf die Entwicklung eines frühen Pankreaskarzinoms zu untersuchen. Ein breites Spektrum an histologischen, immunologischen und molekularbiologischen Methoden wird uns differenzierte Einblicke in die frühe Pankreaskarzinogenese und die diesem Prozess zugrundeliegenden Signalwege geben.

2. Generation (April 2025 - März 2028):

PhD-Student:in: offene Stelle

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.

Projektleitung: Prof. Dr. Martin Gericke

1. Generation (April 2022 - März 2025)

PhD-Studentin: Anne-Kristin Fritsche

Adipositas ist in zahlreichen Organen einschließlich des Pankreas mit chronischer Entzündung assoziiert. Sowohl Adipositas als auch chronische Pankreatitis sind bedeutende Risikofaktoren für das Pankreaskarzinom. Interessanterweise konnte gezeigt werden, dass das intermittierende Fasten (Intervallfasten) im Mausmodell die Inzidenz von Adipositas-assoziierter Brustkrebsentstehung verringert.

Es ist noch ungeklärt, inwiefern das intermittierende Fasten auch die Adipositas-assoziierte Karzinogenese im Pankreas verringert. Außerdem gilt es, die zugrundeliegenden molekularen Mechanismen zu entschlüsseln. Diesen Aufgaben widmet sich dieses Projekt. Wir legen dabei einen besonderen Schwerpunkt auf die Rolle von M2-Makrophagen als zelluläre Mediatoren der Entzündung und Krebsentstehung im Pankreas sowie Interleukin-4-Signalwege.

2. Generation (April 2025 - März 2028)

PhD-Student:in: offene Stelle

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.

Projektleitung: Prof. Dr. Patrick Michl

1. Generation (April 2022 - März 2025):

PhD-Student: Miquel Tibau Baltrons

Neue Forschungsergebnisse deuten darauf hin, dass das intestinale Mikrobiom („Darm-Flora”) Einfluss auf die Pankreaskarzinogenese und das Therapieansprechen nimmt. So konnte gezeigt werden, dass die Gabe von oralen Antibiotika mit Abtöten der Bakterien die Tumorprogression stark verzögerte, wobei der Transfer von Bakterien aus PDAC-tragenden Mäusen diesen Schutz rückgängig machte. Interessanterweise war das Abtöten der Bakterien mit einer immunologischen Umprogrammierung der Tumormikromilieus verbunden (u.a. Reduktion myeloider Suppressorzellen sowie erhöhte Differenzierungs- und Aktivierungsraten von M1-Makrophagen und T-Zellen). Zusätzlich waren die Tumore durch die Hochregulation des PD-1-Rezeptors anfälliger für eine Immuntherapie (Checkpoint-Inhibition).

Diese Ergebnisse weisen auf eine bedeutende Rolle und ein therapeutisches Potential des Mikrobioms bei der Entstehung des Pankreaskarzinoms hin. Wie genau die unterschiedlichen Auslöser der Entzündung, das intestinale und intrapankreatische Mikrobiom und die Entstehung früher (prä)invasiver Neoplasien zusammenhängen, ist aber noch weitestgehend unverstanden. Dieses Projekt zielt daher darauf ab, den Einfluss des intestinalen Mikrobioms auf die entzündungsassoziierte frühe Pankreaskarzinogenese und die Interaktion von entzündlichen Einflüssen und Mikrobiom zu entschlüsseln.

2. Generation (April 2025 - März 2028):

PhD-Student: Miquel Tibau Baltrons

Projektleitung: Prof. Dr. Sebastian Krug, Prof. Dr. Sonja Kessler

1. Generation (April 2022 - März 2025):

PhD-Student: Atul Verma

Tumor-assoziierte Makrophagen (TAM) sind ein wichtiger Bestandteil des entzündlichen Tumormikromilieus, die als maßgebliche Mediatoren der Tumorprogression gelten, aber auch schon im Stroma um präneoplastische PanIN-Läsionen zu finden sind. TAMs stellen ein vielversprechendes Ziel dar, um die Therapieresistenz zu überwinden, die durch das stark immun-evasive Stroma des Pankreaskarzinoms vermittelt wird.

Im Gegensatz zu der gut untersuchten Rolle von TAMs in manifesten Tumoren ist ihre Bedeutung in der frühen entzündungsbedingten Karzinogenese weitestgehend unverstanden. Darüber hinaus konnte gezeigt werden, dass Veränderungen im Fettstoffwechsel eine wichtige Rolle in der Determinierung des Phänotyps von myeloischen Zellen spielen. Der Einfluss myeloischer Zellen auf den Fettstoffwechsel früher pankreatischer Vorläuferzellen im Zusammenhang mit chronischer Entzündung ist jedoch noch nicht geklärt. In diesem Projekt wollen wir den Beitrag der myeloischen Zellen zur entzündungsinduzierten frühen Karzinogenese und das Potenzial für eine therapeutische Modulierung entschlüsseln.

2. Generation (April 2025 - März 2028):

PhD-Student:in: offene Stelle

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

Projektleitung: Prof. Dr. Heike Kielstein, PD Dr. Ivonne Bazwinsky-Wutschke

1. Generation (April 2022 - März 2025):

PhD-Studentin: Elise Arlt

Natürliche Killerzellen (NK-Zellen) sind eine Untergruppe der angeborenen lymphoiden Zellen, die eine zentrale Rolle in der körpereigenen Immunität gegenüber zahlreichen Krebserkrankungen spielen. In mehreren Studien wurden unterschiedliche Defekte von NK-Zellen bei PDAC-Patienten beschrieben. Es konnte auch gezeigt werden, dass die Tumorprogression von PDAC eng mit dysfunktionalen zirkulierenden NK-Zellen assoziiert ist. Unsere eigenen Studien haben gezeigt, dass die Funktionalität und der Phänotyp von NK-Zellen bei Adipositas, einem Zustand chronischer subklinischer Entzündung, beeinträchtigt sind, was zu einer verminderten Immunosurveillance in verschiedenen Krebsmodellen führt. In Übereinstimmung mit diesen Ergebnissen konnte ein signifikanter Rückgang der Anzahl und Funktion von NK-Zellen bei adipösen KC-Mäusen nachgewiesen werden.

In diesem Projekt werden wir die Bedeutung von NK-Zellen in der frühen entzündungsinduzierten Pankreaskarzinogenese entschlüsseln, indem wir ihre Wirkungen sowohl auf präinvasive Zellen als auch auf andere Komponenten des Tumormikromilieus einschließlich des endokrinen Anteils charakterisieren. Darüber hinaus werden wir pharmakologische Modulationsmöglichkeiten von NK-Zellen während der frühen Karzinogenese untersuchen. Wir werden dafür ein breites Spektrum an histologischen, molekularbiologischen und immunologischen Forschungsmethoden einsetzen.

2. Generation (April 2025 - März 2028):

PhD-Student:in: offene Stelle

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.

Projektleitung: Prof. Dr. Jörg Kleeff, Dr. Markus Glaß

1. Generation (April 2022 - April 2025):

PhD-Studentin: Nupur Ohri

Verschiedene Studien haben gezeigt, dass neben dem onkogenen K-Ras molekulare Komponenten wie TGF-α (transforming growth factor α), der EGF-Rezeptor (epidermal growth factor), der PI3K-Signalweg u.a. von Bedeutung für die ADM-Bildung sind und dass der Raf/MEK/ERK-Signalweg wesentlich für die frühe ADM/PanIN-Bildung ist. Neue Erkenntnisse deuten darauf hin, dass die Aktivierung dieser Signalwege in Epithelzellen während der Tumorentstehung und -progression durch parakrine Faktoren aus stromalen Fibroblasten, einschließlich pankreatischer Sternzellen (pancreatic stellate cells, PSC), gefördert wird.

Die genaue Rolle der Stromareaktion und inbesondere der PSCs, die um frühe präneoplastische Läsionen beobachtet werden, ist derzeit jedoch nicht bekannt. Wir wollen in diesem Projekt PSCs identifizieren und ihre Bedeutung für die frühe Pankreaskarzinogenese charakterisieren. Wir werden dafür drei unterschiedlichen Modelle der entzündungsbedingten Pankreaskarzinogenese analysieren und relevante Gene sowohl in vitro als auch in vivo funktionell charakterisieren.  

2. Generation (April 2025 - April 2028):

PhD-Student:in: offene Stelle

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.

Projektleitung: apl. Prof. Dr. Lutz Müller

1. Generation (April 2022 - März 2025)

PhD-Studentin: Tina Seidel

Das Stroma des Pankreas, bestehend aus heterogenen Zelltypen wie PSCs, Fibroblasten und Immunzellen, trägt zur PDAC-Karzinogenese bei, indem des immunmodulatorische Zytokine wie IL-6 und die extrazelluläre Matrix (EZM) bereitstellt. Auch wenn für unterschiedliche Stromazellen verschiedene Rollen bei vollständig transformiertem PDAC nachgewiesen wurden, ist die spezifische Rolle bestimmter Stromazell-Subpopulationen in der Pankreaskarzinogenese nach wie vor ungeklärt.

Neue Studien legen nahe, dass Subpopulationen von pankreatischen Stromazellen ähnliche Eigenschaften wie mesenchymale Stromazellen (MSC) besitzen. Unsere Arbeitsgruppe u.a. haben gezeigt, dass MSCs ein seltener, aber ubiquitärer Zelltyp sind, der immunmodulatorische Eigenschaften besitzt und das maligne Wachstum fördern kann. In diesem Projekt wollen wir native MSCs des Pankreas in den Stadien der Pankreaskarzinogenese charakterisieren und MSC-spezifische immunmodulatorische Eigenschaften definieren, die zur entzündungsinduzierten Entwicklung von PDAC beitragen.

2. Generation (April 2025 - März 2028)

PhD-Student:in: offene Stelle

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. 

Projektleitung: Prof. Dr. Monika Hämmerle

1. Generation (April 2022 - März 2025):

PhD-Studentin: Juliane Blümke

2. Generation (April 2025 - März 2028):

PhD-Student:in: offene Stelle

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.

Projektleitung: Dr. Nadine Bley

1. Generation (April 2022 - März 2025):

PhD-Studentin: Hend Elrewany

2. Generation (April 2025 - März 2028):

PhD-Studentin: offene Stelle

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.

Projektleitung: Prof. Dr. Andrea Sinz, Dr. Stefanie Göllner

1. Generation (April 2022 - März 2025):

PhD-Student: Florian Wolfgang Otto

2. Generation (April 2025 - März 2028):

PhD-Student: Florian Wolfgang Otto

Projektleitung: Prof. Dr. Stefan Hüttelmaier

1. Generation (April 2022 - März 2025):

PhD-Student: Khursheed Ul Islam Mir

2. Generation (April 2025 - März 2028):

PhD-Student:in: offene Stelle

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. 

Projektleitung: Prof. Dr. Tony Gutschner

1. Generation (April 2022 - März 2025):

PhD-Student: Pit Preckwinkel

2. Generation (April 2025 - März 2028):

PhD-Student:in: offene Stelle

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.

Projektleitung: Jun.-Prof. Dr. Michael Böttcher

1. Generation (April 2022 - März 2025):

PhD-Student: Erik Haußner

2. Generation (April 2025 - März 2028):

PhD-Student:in: offene Stelle

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.