Scientific and Central Projects

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CP1: Translational platform for PDAC models and drug response validation

Central Project 1 (CP1) aims at providing complementary and molecularly characterized preclinical PDAC models, which can be chosen and accessed for translational studies by all members of the consortium. To this end, we are setting up a platform for Patient-Derived Xenograft (PDX)-models, organoids and primary cells which are univocally derived from PDAC patients enrolled in the Molecular Pancreas Program (MolPAC) of the UMG. Subtype analyses in translational PDAC models and primary PDAC material from MolPAC patients comprise RNA-seq-based transcriptome analyses, multigene panel sequencing and immunohistochemical stainings.

Moreover, and as a structural measure for treatment studies performed in SP1-7as well as for future investigator-initiated clinical trials, CP1 establishes an in vitro therapy validation platform. This pre-clinical drug platform evaluates the subtype-specificity of therapeutic strategies targeting genome dynamics as identified in SP1-7 in a highly standardized and comparable manner and elucidates the most promising drug combinations for subtype-driven treatment strategies in PDAC.

Generation and molecular characterization of translational PDAC models: Primary PDAC from MolPAC patients will be utilized for the generation of translational PDAC models. Upon expansion and subtype characterization, models are provided to SP1-7 for mechanistic, functional and therapeutic studies. CP2 supports CP1 with data analysis and integration and the establishment of platforms for data storage and exchange.
Workflow of the in vitro therapy validation platform: We determine the ATP-content of PDAC cells, subject them to automated translucent microscopy (Celigo cytometer) and perform γH2AX- and TUNEL stainings to determine cell viability, cell proliferation and DNA damage/cell death, respectively.

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

Jennifer Appelhans (Institut für Pathologie)
Mark-Sebastian Bösherz (Institut für Pathologie)
Christin Kellner (AG Heßmann)
Waltraut Kopp (AG Heßmann)
Anna Magerhans (AG Dobbelstein)
Sercan Mercan (AG Ellenrieder)

Further information on the AG Heßmann, the Institut für Molekulare Onkologie and the Institut für Humangenetik is available on their respective websites.

CP2: Biomedical Informatics Support Platform (BISP)

1. Initial consulting for the NGS experiment 2. Samples are registered in SEEK and a first sample QC report is generated. 3. NGS-libraries are performed according to SOPs defined for the CRU 5002 and a second library QC is generated. 4. Samples are sequenced on the Illumina platform according to standards defined for the CRU 5002. 5. Data preprocessing is performed using bcl2fastq including demultiplexing and trimming and a third data QC is generated and stored in SEEK. 6. Generated data and reports are available for the members of the CRU 5002 on the SEEK platform. 7. CP2 supports the analysis of the NGS data.

In the framework of the CRU 5002 the Biomedical Informatics Support Platform (BISP) of CP2 is responsible for providing IT structures, bioinformatic methods and pipelines to store, analyse and integrate the numerous phenotypic, genomic and functional data generated in SP1-7 and CP1. Further, the data of the CRU is merged and analyzed in the context of the comprehensive clinical annotations gathered in the MolPAC program.

In this central project, Next-Generation-Sequencing studies and transcriptome analyses are performed on a central platform for all genomic analyses required throughout the consortium as well as for translational PDAC models established in CP1.

In addition, CP2 offers statistical consulting to all scientific sub projects for the meaningful planning and execution of their genomic experiments. CP2 is responsible for the execution of comprehensive bioinformatic analyses and the qualified interpretation of genomic data.

Finally, CP2 integrates molecular subtyping data collected within the CRU 5002 with published data on PDAC subgroups and supports CP1 in comparing PDAC PDX-models and organoids for their subtype consistency.

Tim Beißbarth, Abteilung für Bioinformatik, UMG
Gabriela Salinas, NGS - Integrative Genomics Core Unit (NIG), UMG
Ulrich Sax, Institut für Medizinische Infromatik, UMG

Christian Bauer (AG Sax)
Theresa Bender (AG Sax)
Karly Conrads (AG Beißbarth)
Jaqueline Fink (AG Salinas)
Martin Haubrock (AG Beißbarth)
Fabian Ludewig (AG Salinas)
Susanne Luthin (AG Salinas)
Malte Sahrhage (AG Beißbarth)

Further information on the Translationale Verbundforschung, the Department of Medical Bioinformatics and the NGS - Integrative Genomics Core Unit (NIG) is available on their respective websites.

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) isthe 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- and 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 CRU 5002 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 potential of interfering with these genome dynamic alterations and hence sought to elucidate whether and how the ARID1A status can be considered for stratification-based therapy inPDAC treatment.

PI: Elisabeth Heßmann, Klinik für Gastroenterologie, gastrointestinale Onkologie und Endokrinologie, UMG
Team: Zhe Zhang (AG Heßmann)

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

SP2: Exploiting oncogenic transcription factor complexes in misp53 PDAC subtypes

The high aggressiveness as well as the chemoresistance of PDAC are significantly determined by the diverse genomic alterations occurring throughout disease development and progression. More than 75% PDAC tumors exhibit genetic alterations in TP53 tumor suppressor functions. In particularly, missense TP53 mutations are more prevalent among the PDAC patients with high-grade and metastatic cancer. However, the extent to which these missense TP53 mutants determine unfavorable prognosis and therapeutic outcome in PDAC remains unclear. SP2 aids at gaining mechanistic insights into distinct missense TP53 mutants and their consequences on genome dynamic alterations driving PDAC aggressiveness and therapy resistance.

Ramona Schulz-Heddergott, Institut für Molekulare Onkologie, UMG
Shiv K. Singh, Klinik für Gastroentreologie, gastrointestinale Onkologie und Endokrinologie, UMG

Tamara Isermann (AG Schulz-Heddergott)
Laura Urbach (AG Singh)

Further information on the Schulz-Heddergott Group and the AG Singh is available on their respective websites.

SP3: Epigenetic regulation and therapeutic targeting of PDAC subtypes with aberrant drug metabolism

Chemoresistance constitutes a major cause for the dismal prognosis of PDAC. Despite significant preclinical and clinical efforts to maximize therapeutic efficacy in PDAC treatment, the detailed mechanisms underlying therapy resistance remain largely elusive. Strikingly, there is a huge discrepancy between the antineoplastic effects of anti-cancer drugs in established cell lines in vitro and in patients. For instance, the antimetabolite gemcitabine is usually well tolerated in PDAC patients, but has very limited effectiveness to shrink pancreatic tumors and prolong survival. Drug metabolizing enzymes such as cytosolic 5'-nucleotidase 1A (NT5C1A) and cytidine deaminase (CDA) might define a clinically highly relevant molecular subgroup of PDAC patients that could be exploited for tailored treatment approaches. Based on previous data from our group, we hypothesize that chromatin dynamics define novel therapeutic PDAC subgroups that may correlate or partially overlap with existing molecular subtypes. In addition, we propose that patient subgroups can benefit from targeted therapeutic interventions in combination with selected cytotoxic compounds. SP3 analyses chromatin regulatory networks of subtype-specific drug metabolism pathways in human and murine PDAC in collaboration with other KFO5002 projects and test whether epigenetic targeting has therapeutic potential to disrupt these pathways in PDAC using a variety of different genetically engineered model systems and state of the art pharmacokinetic and pharmacodynamics assays.

PI: Albrecht Neeße, Klinik für Gastroentreologie, gastrointestinale Onkologie und Endokrinologie, UMG

Christoph Ammer-Herrmenau (AG Neeße)
Nina Pfisterer (AG Neeße)

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

SP4: GSK3βhigh subtype-specific DNA repair mechanisms and resistance in PDAC

GSK3β is a multifunctional serine/threonine kinase, which due to its broad substrate specificity, is involved in numerous cellular processes, e.g. glucose metabolism, proliferation and stem cell identity. Changes in GSK3β expression, localization and kinase activity have been reported in various human diseases, e.g. type-2 diabetes mellitus, Alzheimer’s disease and cancer. In cancer, GSK3β can exert both tumor suppressor and promoter functions depending on the cellular and molecular context. In addition to the well-established tumor suppressor functions of GSK3β, increasing evidence also supports oncogenic activities of the kinase in various epithelial and non-epithelial malignancies, e.g. mixed lineage leukemia, glioblastoma and oral cancer, in which activation of the kinase promotes cancer growth and metastasis as well as chemoresistance. We and others have univocally shown the powerful oncogenic properties of GSK3β-signaling activation in pancreatic cancer (PDAC), where it favors acquisition of a poorly differentiated and highly aggressive phenotype. Within SP4, we want to further understand its functions, especially focusing on the involvement of GSK3β in DNA-repair mechanisms. Hereby is of special interest how different epigenetic alterations can influence this pathway and serve as a predictor of the GSK3β inhibition in PDAC therapy. The platform of the KFO 5002 provides with its multiple models the necessary basis to evaluate the potential of GSK3β inhibition in the stratification of patients.

PI:  Volker Ellenrieder, Klinik für Gastroentreologie, gastrointestinale Onkologie und Endokrinologie, UMG

Team: Geske Schmidt (AG Ellenrieder)

Further information on the AG Ellenrieder 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.

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

Adi Danieli (AG Papantonis)
Teona Midelashvili (AG Conradi)
Tiago De Oliveira (AG Conradi)

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

SP6: Understanding TGFβ driven mitotic errors and chromosomal instability in SMAD4-deficient PDAC subtypes

Whole chromosome instability (W-CIN) is a hallmark of cancer and is defined as an increased rate of chromosome missegregation during mitosis leading to evolving aneuploidy. By perpetually altering the genetic composition of cancer cells W-CIN can fuel clonal evolution of tumors, tumor progression and the development of therapy resistance. The sub-project 6 focuses on the role of TGFβ signaling for the induction of W-CIN in pancreatic cancer. In particular, we hypothesize that PDAC subgroups characterized by high TGFβ signaling and by loss of SMAD4 are prone for the induction of chromosomal stability, which supports tumor progression, tumor aggressiveness and therapy resistance. The sub-project 6 will systematically investigate the presence and the mechanisms of W-CIN in PDAC, which will lead to a first definition of PDAC sub-types characterized by mitotic errors and W-CIN. Furthermore, we aim to elucidate the nature of mitotic errors present in chromosomally unstable PDACs, both in cell lines and in PDX-derived cells. By interfering with TGFβ signaling we will develop experimental routes to suppress CIN in PDAC cell models to directly address the question for the role of CIN in acquiring aggressive tumor phenotypes and in mediating resistance towards clinically relevant therapy regimens.

PI: Holger Bastians, Institut für Molekulare Onkologie, Sektion Zelluläre Onkologie, UMG

Simran Kaur (AG Bastians)
Atmika Paul (AG Bastians)

Further information on the Bastians Group is available on their website.

SP7: Exploiting subtype-specific HSP90 targeting for sensitization of PDAC cells towards platinum-based therapy

The chemotherapy of pancreatic carcinoma often involves cisplatin, a drug that crosslinks DNA. If cancer cells fail to repair such crosslinks, they often die, resulting in a favorable tumor response. However, efficient repair of cisplatin-mediated DNA lesions result in cancer cell resistance and further tumor growth. To improve the efficacy of cisplatin, we are combining it with additional drugs that target heat shock proteins. Such heat shock proteins help to shape proteins shortly after their synthesis in the cell. A class of proteins that depends on heat shock proteins to a particularly high extent comprises the repair machinery for DNA crosslinks, called the Fanconi anemia pathway. Thus, targeting heat shock proteins with HSP90 antagonists results in the degradation of Fanconi anemia proteins, and thus renders the cell unable to repair cisplatin-induced DNA lesions. As a result, cancer cells respond to cisplatin with greater efficacy. However, the response to such drug combinations varies between individual tumor cells, and we are currently trying to find out the genetic features that determine their sensitivity. On the long run, we hope to improve such therapeutic combinations for patient care, and to find additional targets for enhanced therapeutic efficacy.

PI: Matthias Dobbelstein, Institut für Molekulare Onkologie 

Lab member: Katharina Ewers (AG Dobbelstein)

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

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