CP1: Translational platform for PDAC models and drug response validation

In order to study the mechanistic, functional and therapeutic consequences of subtype-specific and subtype-overlapping genome dynamic alterations in PDAC, the consortium relies on molecularly characterized patient-derived PDAC models suitable for comprehensive applications ranging from detailed mechanistic studies to pre-clinical drug testing. To this end, CP1 has established a translational PDAC model platform comprising Patient-Derived-Xenograft (PDX) models, PDX-derived primary PDAC cells (CDX) and patient-derived-organoid (PDOs) models for joint utilization within and beyond the CRU5002. PDAC models are generated from PDAC patients enrolled in the Molecular Pancreas Program (MolPAC) of the UMG and reflect all disease stages. In cooperation with CP2, we conduct thorough molecular characterization of the primary PDAC specimen and the translational models at the genomic and expression (transcriptome and immunohistochemistry) level. Further, CP1 functions as the interface of the CRU5002 and the Molecular Tumor Board (MTB) of the UMG and benefits from the MTB pipeline as a temporally distinct second source of PDAC samples and models. Finally, CP1 offers an in vitro PDAC model platform for basal functional characterization of PDO and CDX models and standardized and quality-controlled assessment of drug (combination) responses. Together, CP1 envisions to substantially support the CRU5002 in dissecting the biological significance and the therapeutic consequences of genome dynamics in PDAC and to speed up the translational potential of CRU5002 findings.

PIs:
Elisabeth Heßmann, Klinik für Gastroenterologie, gastrointestinale Onkologie und Endokrinologie
Matthias Dobbelstein, Institut für Molekulare Onkologie
Jochen Gaedcke, Klinik für Allgemein-, Viszeral- und Kinderchirurgie
Silke Kaulfuß & Prof. Dr. Bernd Wollnik, Institut für Humangenetik
Philipp Ströbel, Institut für Pathologie

Team:
Jennifer Appelhans (Ströbel Group)
Christin Kellner (Hessmann Group)
Waltraut Kopp (Hessmann Group)
Sercan Mercan (Ellenrieder Group)
Joana Oschwald (Hessmann Group)
Sebastian Schimkowiak (Dobbelstein Group)
Jovan Todorovic (Ströbel Group, GEROK position)
Lennart Versemann (Hessmann Group)
Chan Rong Lai (Schneider Group)
Claudia Hartmann (Schneider Group) 

If you are interested in our translational PDAC models, please contact elisabeth.hessmann(at)med.uni-goettingen.de.

SP1: Characterizing genome dynamics in ARID1A-deficient PDAC subtypes

38% of PDAC are characterized by alterations in genes encoding chromatin regulatory proteins, particularly members of the SWItch/Sucrose Non-Fermentable (SWI/SNF) family. Given the widespread loss-of-function mutations of different subunits of the SWI/SNF complex in a plethora of malignancies, members of this chromatin remodeling complex are referred to as pivotal tumor suppressors. AT-rich Interactive Domain-containing protein 1A (ARID1A) is the most frequently altered subunit of the SWI/SNF complex in PDAC and has been associated with an aggressive PDAC phenotype and a bad disease outcome. Importantly, in other tumor entities, ARID1A-deficiency is connected to increased sensitivity towards PI3K/AKT-, ATR-, PARP- HDAC- or EZH2-inhibition, thus suggesting assessment of the ARID1A status as a promising therapy-predictive strategy in cancer treatment. However, whether ARID1A deficiency also predicts for certain therapeutic vulnerabilities in PDAC remains mainly elusive. SP1 aids at filling this gap and utilizes the structural and material-based resources as well as the diverse scientific expertise of the CRU5002 to explore the mechanistic background and the functional implications of genome dynamic alterations that particularly characterize ARID1A-deficient PDAC subtypes. Moreover, we investigate the therapeutic consequences of ARID1A-status specific genome dynamic alterations and hence sought to elucidate whether and how the ARID1A status can be considered for stratification-based therapy in PDAC treatment.

PI: Elisabeth Hessmann, Department for Gastroenterology, Gastroinestinal Oncology, and Endocrinology, University Medical Center Göttingen

Team: 

Jessica Spitalieri
Christin Kellner
Darina Kiriluk
Waltraut Kopp
Denise Schlösser

Maria Ulisse 
Jiska Ziegler 
 

Further information on the AG Heßmann is available on their website.

SP5: Metabolic impact on chromatin topology in subpopulation-derived PDAC organoids

A hallmark of both tumorigenesis and cancer progression is the metabolic reprogramming of cancer cells, and an interest in targeting metabolic cancer traits has resurged. Specifically, as regards pancreatic cancer, the TCGA (The Cancer Genome Atlas) classification of PDACs was recently found to align well with distinct metabolic states. Classical PDAC tumors mostly rely on lipogenic metabolism, while the more aggressive squamous/ mesenchymal PDACs predominantly rely on glycolysis, with the two subtypes also displaying striking differences in glucose and glutamine utilization, as well as in mitochondrial function. These differences suggest differential sensitivity of PDACs to inhibitors targeting glycolysis, glutamine metabolism, lipid synthesis or redox balance. This coincidence between PDAC subtypes and metabolic states becomes even more relevant once one considers that specific metabolic pathways directly affect global chromatin methylation and acetylation levels and may, thus, contribute to the dramatic dysregulation of epigenetic profiles in tumours. It is exactly this link that our project will investigate: by combining studies of spatial genome organization, cis-element mapping, and single-cell transcriptomes in patient-derived PDAC organoids we aim at uncovering regulatory circuits that can be targeted for therapeutic intervention.

PIs:
Lena Conradi, Klinik für Allgemein, Viszeral- und Kinderchirurgie, UMG
Argyris Papantonis,  Institut für Pathologie, UMG

Team:

AG Conradi:
Tiago De Oliveira
Birgit Jünemann
Henrik Spahn
Tobias Tacke
Sara Younes
Fabio Gätje
Alexandra Schmitt
Kelvin Lai
Theon R. Tesch
Teona Midelashvili

AG Papantonis:
Adi Mackay

Further information on the AG Papantonis and the AG Conradi is available on their respective websites.

SP7: Synergistic PDAC cell ablation by inhibiting CDKs and oncogenic signaling

Besides classical chemotherapy, the use of cyclin dependent kinase (CDK) inhibitors for treating pancreatic cancer is subject to intense investigation. Our project explores the efficacy of drug combinations that comprise such inhibitors. We are testing the hypothesis that inhibitors of cyclin dependent kinase 4 (CDK4) can eliminate PDAC cells and tumors in synergy with additional inhibitors that target oncogenic signalling pathways or chromatin modifiers. This hypothesis addresses a drug synergy, similar to our research during the first funding period (Ewers et al., 2021). It is based on our previous findings that the depletion or inactivation of signalling components perpetuates the cell cycle arrest imposed by inhibitors of CDK4. Mechanistically, the cell cycle is arrested by CDK4 inhibition. Under most circumstances, this arrest is only transient. Simultaneously interfering with oncogenic signaling, however, permanently precludes further proliferation. We are now planning to assess the genetic tumor cell specificities that determine the degree of this drug synergy, comparing PDAC-derived cell lines, patient-derived cells and organoids of the CRU5002 cohort. In this context, we are assaying the transcriptome and genome-wide chromatin modifications. Taken together, the project aims at improving PDAC therapy with CDK4 inhibitors, through the identification of synergistic drug combinations.

PI: Matthias Dobbelstein, Institut für Molekulare Onkologie 

Team:

Maj-Britt Paulsohn 

Further information on the Institute of Molecular Oncology is available on their website.