Collaborative Research Centre

Project leader
Christoph Klein
Experimental Medicine and Therapy Research, University of Regensburg

Since publication of the famous Vogelgram the acquisition of metastatic traits has been a matter of heated debate. For decades it was deemed obvious that the metastasis-founder cells arise from the most advanced and aggressive clone of a primary tumour and disseminates late - possibly the day before surgical resection of the primary tumour. Comparative sequencing of primary tumours and metastases and full assessment of intratumoural heterogeneity has complicated interpretations and the analysis of disseminated cancer cells (DCCs) added new layers of complexity by revealing early dissemination and acquisition of genetic changes outside the primary tumour. However, for the development of novel adjuvant therapies to prevent early metastatic colony formation and to eradicate candidate metastasis founders, it is essential to understand the genetic, epigenetic and functional armament of DCCs. Here, we will address this by a three-step approach. Firstly, we will establish cell lineage trees of longitudinal samples from patients progressing from M0-stage disease to M1-stage disease. We will identify the DCC(s) located closest to the root of the metastatic branch of the cell lineage tree and perform detailed genetic characterization. Secondly, we will mine the transcriptomes and genomes of DCCs to identify molecular mechanisms associated with early metastatic colonization. Thirdly, we will develop cellular models representative of metastasis founders for functional evaluation and therapeutic targeting.

See also: https://www.experimentelle-medizin.de/en/research#

Project leaders
Rainer Spang
Institute for Functional Genomics, 
University of Regensburg

Lothar Häberle
University Hospital Erlangen, 
Department of Gynecology

Today we have tumor atlases such as TCGA, MSK-IMPACT, and ICGC that show the genomic landscapes of many primary tumors and metastatic lesions. These data consist of static snapshots of the tumors at the time of biopsy or resection. Tumor progression and metastatic colonization, however, are dynamic processes. Some events happen early in history, others late. Some events can set the stage for colonization of a distant organ, while others such as driver mutations can change the course of a tumor’s history entirely. Events can be genomic such as mutations and copy number alterations, they can be immunological such as the invasion of the tissue by certain immune cells, they can be functional such as the upregulation of key proteins, or they can be clinical such as the occurrence of complications or patient’s death. Most importantly, the formation of a metastasis within in a specific organ is also a key event during systemic progression. We have an atlas of these events, here we want to compliment it by a history book. In such a history book we can seek answers to questions such as which alterations are early and which are late, which mutations affect the course of tumor evolution, or which mutations associate with the colonization of a specific organ. We will use our algorithm MHN (Schill 2018) to annotate mutations by their timing (early/late), by a cancer driver score, and by possible associations with metastasis. While data for genomic alterations is readily available in public databases this collaborative research center (CRC) studies colonization and its functional and immunological foundations. We will collaborate with several projects and position events such as infiltration by a certain type of immune cells (e.g. CD8+ T-cells) or the up regulation of a specific protein that drives colonization in the framework of genomic progression. Since information on immunological features and the expression of key molecules studied in this CRC are usually not available in public genomic atlases, we will also collaborate with the ongoing PRAEGNANT study (Fasching 2014) which generates sequences of up to 850 pairs of primary tumor and metastasis genomes (panel sequencing). Importantly for these samples tissue material is available at the Institute of Pathology at FAU and molecular and immunological characterizations can be generated to complement the genomic data. The PRAEGNANT study records detailed clinical follow up data such that also clinical events such as complications and death will be part of the model.

Project leaders
Thomas Brabletz 
Department of Experimental Medicine 1, 
FAU Erlangen-Nürnberg

Dimitrios Mougiakakos 
Department of Medicine 5, 
FAU Erlangen-Nürnberg

Metastatic colonisation requires a dynamic adaption of cancer cells to the permanently changing conditions of the tumour environment. This is enabled by the activation of the embryonic epithelial to mesenchymal (EMT) program, which provides the necessary plasticity to cancer cells. We and others have demonstrated that this plasticity also includes a permanent adaptation of metabolic processes. In project A03 we will address how EMT-activation is coupled to metabolic changes in metastatic colonisation, with the aim to identify molecular bottlenecks as novel therapeutic targets. We will identify and characterize EMT-dependent metabolic processes, how EMT factors regulate metabolic processes (e.g. a switch between central energy consumption pathways), explore ways of targeted interference and validate the findings in human cancer.

See also: https://www.em1.med.fau.de/

Project leaders
Simone Brabletz
Department of Experimental Medicine 1, 
FAU Erlangen-Nürnberg

Christian Schmidl 
Regensburg Center for Interventional 
Immunology (RCI), 
University of Regensburg

In the last 15 years, the Brabletz lab characterised Zeb1 as an EMT-transcription factor that is mediating tumour cell plasticity and thus enabling tumor progression and metastatic colonisation. Christian Schmidl’s lab that has great expertise in the field of chromatin-dependent gene regulation and next-generation sequencing approaches. The process of metastasis is described to be accompanied by substantial reprogramming of the cancer cell's gene-regulatory landscape. Zeb1 knock-out cell lines from a genetic mouse model of pancreatic cancer (KPC) are trapped in an epithelial phenotype and exhibit very low lung colonisation capacity compared to plastic Zeb1 wt lines. Since Zeb1 functions as a transcriptional co-activator mainly in putative enhancer regions, we now aim to characterise the enhancer landscape of the above-mentioned cell lines to identify Zeb1 dependent enhancers and their target genes, and test their relevance for colonisation and metastasis. We will validate our findings in human cell lines and organoids, thus advancing our understanding about molecular mechanisms of metastasis, which will provide the prospect of novel prognostic tools and putative targets for therapeutic strategies.

See also: https://www.em1.med.fau.de/

https://www.rcii.de/en/research/career-development-program/junior-research-group/

Project leaders
Gernot Längst
Institute for Biochemistry, Genetics and 
Microbiology, University of Regensburg

Hedayatollah Hosseini
Experimental Medicine and Therapy Research, University of Regensburg

For metastasis, cancer cells need to disseminate to a distant site and start formation of a colony. Epithelial-mesenchymal transition (EMT) at the primary site and mesenchymal-epithelial transition (MET) at the distant site are concepts to explain this plasticity. The precise molecular mechanisms governing this plasticity are debated but in all cases cancer cells need to activate proliferation to form a metastasis. We have recently found in the Balb-NeuT model of breast cancer that the chromatin-remodeling factor Baz2a is highly upregulated in migratory breast cancer cells that display stemness properties. Furthermore, Baz2a is upregulated in small micrometastases, and downregulated in highly proliferative advanced primary tumors and metastases. Baz2a is a subunit of the chromatin remodeling complex, NoRC that plays an important role as the epigenetic regulator of gene expression by inducing changes in nucleosome positioning, histone deacetylation and DNA methylation. . Baz2a binds to a non-coding RNA (pRNA) that regulates the function and genomic targeting of the com-plex. This pRNA exists in a processed and non-processed form, exerting different functions. The non-processed form is present in stem cells and cells with stem cell potential, whereas the processed form predominantly exists in differentiated cells.  In this project we aim to address the molecular role of Baz2a containing remodeling complexes in the process of metastasis, addressing its role in inducing stemness and survival of breast cancer cells after dissemination, and its impact on colonization at the recipient site. We also aim to screen for small molecule inhibitors of Baz2a RNA interaction to block its tumorigenic potential and to evaluate these in a mouse breast cancer model.

See also: https://www.ur.de/laengst/home/index.html

https://www.experimentelle-medizin.de/en/research

Project leaders:
Christina Hackl
Department of Surgery, 
University Hospital Regensburg

Gunter Meister
Department of Biochemistry I,
University of Regensburg

The development of metastases from disseminated cancer cells requires adaptation to potentially hostile environments. One factor creating a hostile environment is chemotherapy, e.g. adjuvant chemotherapy after removal of a primary malignancy. Adaptation of early disseminated cancer cells and formation of metastatic colonies resulting in recurrent disease is a main reason for cancer mortality. In this setting, low-dose metronomic therapy (LDM), which is the daily, long-term low-dose administration of chemotherapeutic drugs, has been successful in patients refractory to standard chemotherapy (Romiti 2017). Mechanisms of LDM include suppression of tumor-angiogenesis, stimulation of anticancer cytotoxic T-cell responses or induction of tumor dormancy (Kerbel 2013, Kerbel and Shaked 2017, Maiti 2014). Non-coding RNAs play a crucial role during colonization of disseminated cancer cells and the development of cancer metastasis under therapy (Drak Alsibai and Meseure 2018). However, only very little is known about the role of regulatory RNAs such as circular RNAs (circRNAs) or long non-coding RNAs (lncRNAs) during LDM therapy. Moreover, several lncRNAs have been found to encode for micropeptides, most of them with unknown functions. We therefore plan to assess how non-coding RNAs and micropeptides derived from lncRNAs affect metastatic colony formation during LDM. We hypothesize that the highly complex and plastic ‘non-coding’ transcriptome is an important regulator of metastatic colony formation and response to or escape from chemotherapy.

Project leaders:
Philip Gribbon 
Fraunhofer ITMP ScreeningPort, Hamburg

Kamran Honarnejad 
Fraunhofer ITEM-R, Personalized Tumor Therapy, Regensburg

Joachim Wegener
Fraunhofer EMFT/ Institute of Analytical Chemistry, Chemo- and Biosensors, University of Regensburg

The recently assessed poor success rates of drug candidates targeting metastatic progression in clinical trials has been, at least in part, attributed to reductionist approaches during early preclinical drug discovery which are often hampered by poor recapitulation of tumor microenvironment. More recently, the development of 3D patient tumor organoid models and multicellular co-culture systems has improved clinical drug response predictability. Thus, the use of complex cellular models including metastatic niches for target identification and high-throughput screening (HTS) holds great promise for discovery of therapies with improved efficacy and response rates.
In order to support the discovery of clinically relevant treatments against metastatic progression, the goal of this project is to develop complex 3D in vitro models and tailored cell-based assays. These will be used to emulate and study the fundamental processes during early metastasis for use in drug screening campaigns to discover potential therapeutic interventions. The project has three topical pillars that complement each other providing an unprecedented in vitro platform: (i) Development of patient-derived 3D tumor organoid models including their adaptation to high-throughput and high-content screening requirements followed by proof of concept drug sensitivity screens for preclinical drug discovery, drug repurposing and precision therapy; (ii) Establishment of physiologically relevant, homotypic or heterotypic iPS-based in vitro models that represent sites of metastatic colonization most relevant to breast, pancreas, melanoma and colorectal cancers; (iii) Extending and combining the range of available readout technologies to monitor the 3D in vitro models under static conditions, during experimental encounter of tumor cells with potential metastatic niches and when these are challenged by state of the art small molecule drug libraries. The experimental readouts include target-based endpoint assays but also phenotypic, imaged-based or integral, label-free and time-resolved approaches that are developed into a modular platform. Data will be analysed by advanced bioinformatics approaches to interrogate and reveal the underlying biological processes of metastatic niche formation, maintenance and colonization. Thereby, this project seeks to contribute to an improved understanding of early metastasis and efficient discovery of intervening drugs hoping to bridge the predictability gap between the efficacy of compounds in high-throughput screens and their outcome in clinical trials. Specifically, our aims will be addressed through collaborations with several projects of the TRR 305 based on their individual needs to discover novel pharmacological interventions targeting metastatic colonization-associated mechanisms.

Project leader:
Thomas Brabletz 
Department of Experimental Medicine 1, 
FAU Erlangen-Nürnberg

Tumour-infiltrating cells of the myeloid compartment are crucial determinants of tumour progression towards metastasis. Particularly tumor associated macrophages (TAMs) where described to exert both tumour/metastasis promoting and suppressing functions. The underlying molecular basis is not fully understood. Our preliminary data indicate that the EMT transcription factor Zeb1 defines a subpopulation of TAMs with strong effects on the colonization-efficacy of disseminated cancer cells. The aim in project B01 is to understand, how Zeb1 determines the generation of TAM-subpopulation and to characterize the Zeb1+TAM subpopulation. We will apply transplantation and genetic mouse tumour models, scRNA sequencing, ex vivo organ slice culture/microscopy and organoid-TAM co-cultures to address these questions, and will validate the findings in human cancer.

See also: https://www.em1.med.fau.de/

Project leader:
Falk Nimmerjahn 
Department of Biology, 
FAU Erlangen-Nürnberg

Tumor-immune cell interactions can modulate tumor establishment and metastasis. Depending on the cytokine environment macrophages and other myeloid cells can fuel inflammation or trigger resolution of inflammation resulting in suppression of (tumor)immunity and tissue repair. In line with this notion, tumor associated macrophages (TAM) can support or limit tumor growth and metastasis depending on the organ environment. The project aims at (1) identifying organ specific roles of bone marrow derived versus tissue resident macrophages in modulating tumor growth and early metastatic colonisation, (2) at characterizing and alter the phenotype of TAM subpopulations present in tumors growing in different organ environments, and (3) at studying the role of myeloid effector cells in supporting or limiting human primary melanoma and early metastatic melanoma colonisation and growth in humanized mice in vivo.

Project leader:
Diana Dudziak 
Department of Dermatology, 
FAU Erlangen-Nürnberg

The formation of metastases in malignant melanoma is associated with a very bad prognosis for melanoma patients. Unfortunately, our current understanding of this process in malignant melanoma is still very limited. The type and functionality of immune cells in a distinct tumour is a matter of intense research. Further understanding of the influence of the tissue microenvironment on cell migration, infiltration, and metastases formation is urgently needed for the development of specific therapies targeting the tumour metastases, as such a therapy would have a strong effect on the patients' prognosis and quality-of-life. Dendritic cells (DCs) exert an important role in the induction and guidance of innate and adaptive immune responses to invading pathogens as well as to tumour cells. Although the role of DCs has been studied in solid primary tumours, their precise role during the metastatic colonisation and the unscathed growth of melanoma metastases in a new tissue microenvironment is largely unknown. Since we have previously shown that the tissue microenvironment strongly influences the DC functionality, we hypothesise that it might negatively influence the DC function during metastatic colonisation of secondary organs. Therefore, the main goal of this project is to characterise the DC subsets and their phenotype, as well as to identify the influenced immunomodulatory pathways in the DCs during development of primary melanomas and the subsequent metastatic processes including colonisation of vital organs. We will further validate our key findings in the human system concerning the influence of the tissue microenvironment on the overall DC function and the involved key regulatory pathways as this will pave the road to develop therapies to overcome these negative regulatory mechanisms for the patients' benefit.

Project leaders:
Markus Feuerer / Thomas Hehlgans
Department of Immunology,
Regensburg Center for Interventional Immunology (RCI), 
University of Regensburg

Compelling evidence has accumulated that IL-33, a member of the IL-1 family of cytokines, and its corresponding receptor ST2 are important in cancer progression and metastasis. However, the cellular source of IL-33 as well as the cellular and molecular signaling pathways induced in ST2-positive immune cells in the context of tumour progression and early metastasis are not well understood. The current view is that IL-33 acts as an alarmin, which can be produced by epithelial barrier tissues and released upon tissue damage. Recent data by us and others suggest that IL-33 is mainly expressed under homeostatic conditions by subsets of mesenchymal stromal cells, specifically, fibroblast reticular cells (FRCs) in lymph nodes and peripheral tissues, such as adipose tissue, lung and bone marrow.  
IL-33 signaling is mediated by the receptor ST2, which is expressed by different immune cells including tissue-resident regulatory T cells (tisTreg cells), CD4 T-helper cells type 2 (TH2 cells) and group 2 innate lymphoid cells (ILC2 cells). Current knowledge about the functional role of the IL-33/ST2 receptor-ligand system during early metastasis is very limited. Regulatory T cells and fibroblasts both have been shown to contribute to metastasis formation. We hypothesize that the IL-33/ST2 axis, through the interaction of fibroblastic stromal cells and tissue resident regulatory T cells, plays an important role in early metastasis. This axis could create a pro-metastatic stromal microenvironment allowing early niche seeding. The aim of this project is to functionally characterise the cellular and molecular mechanisms of the IL-33/ST2 axis important for early metastasis in order to develop novel interventional therapeutic strategies. This will be achieved by the functional analysis of different genetic mouse model systems and human specimens. The therapeutic avenue will be addressed by screening for small molecule inhibitor compounds interfering with IL-33/ST2 signaling pathways. 

Project leaders:
Marc Stemmler 
Department of Experimental Medicine 1, FAU Erlangen-Nürnberg

Nathalie Britzen-Laurent 
University Hospital Erlangen,
Department of Surgery,
Translational Research Center

The lab’s focus is to identify key mechanisms of tumour progression and metastasis driven by the epithelial-mesenchymal transition (EMT) program. The microenvironment at metastatic target sites determines the success of disseminating tumour cells to establish a metastatic colony. In metastasis of pancreatic ductal adenocarcinoma (PDAC) cancer associated fibroblasts (CAFs) are forming a very heterogeneous tumour microenvironment. This is reflected by activation of the EMT-inducing transcription factor ZEB1 in only a subset of CAFs. We hypothesize that ZEB1 is a crucial determinant of CAF subtype specification and function that drives disease progression. We will identify and analyse different CAF subpopulations and the role of ZEB1 in the process of colonization. We apply transplantation and genetic mouse tumour models, scRNA sequencing, ex vivo organ slice microscopy and human PDAC organoid-CAF co-cultures to address these hypothesis. With our findings on specific CAF subtypes, we hope to identify new therapeutic approaches targeting pro-tumourigenic functions of the microenvironment during colonization.

See also: https://www.em1.med.fau.de/

Project leaders:
Elisabeth Naschberger 
Department of Surgery, 
FAU Erlangen-Nürnberg

Claudia Günther 
Department of Medicine 1, 
FAU Erlangen-Nürnberg

Colorectal cancer (CRC) is among the major death-causing cancers worldwide and distant metastases are the main cause of cancer-related death in the respective patients. The mutual interaction of disseminated cancer cells (DCCs) with blood vessel endothelial cells (ECs) is involved in metastatic colonization of hostile tissues, but it is not known whether it may foster or prevent the growth of DCCs. We previously uncovered that tumor blood vessels, in contrast to the current knowledge, not only promote but under certain conditions also suppress tumorigenesis. We found that this function requires SPARCL1, a matricellular protein which was highly associated with quiescent ECs in mature vessels of normal tissues, including colon, stomach and lung. Of note, SPARCL1 is released from quiescent ECs by classical secretion and therefore acts as a para- and autocrine mediator. Functional studies demonstrated that SPARCL1 regulates blood vessel homeostasis by inhibiting EC proliferation and migration. Interestingly, high SPARCL1 expression was observed in CRC tissues with a prognostically favorable Th1-like tumor immune microenvironment (Th1-TME) and reduced angiogenic activity. In contrast, SPARCL1 expression was downregulated and low in aggressive CRCs devoid of a Th1 immune response but with high angiogenic activity. On a functional level, SPARCL1 inhibited proliferation and migration of endothelial cells and CRC tumor cells. These findings indicated that SPARCL1 represents a novel angiocrine suppressor of neo-angiogenesis and tumor progression. Accordingly, the central hypothesis of this proposal is that angiocrine SPARCL1 inhibits expansion of single DCCs residing in distant organs and by this mechanism actively counteracts loco-regional and distant metastasis. Within this project, we will analyze whether and how SPARCL1 actively counteracts metastatic colonization in distant organs. The long-term perspective is to establish SPARCL1 as a novel diagnostic marker to predict the risk of metastasis and to discover novel functions of matricellular proteins that could be targeted for future therapeutic intervention of metastasis.

Project leader:
Melanie Werner-Klein
Experimental Medicine and Therapy Research,
University of Regensburg

Melanoma spread to lymph nodes of the regional basin is a major predictor for melanoma outcome. Since regional lymph nodes are often resected, they offer the unique opportunity to catch human disseminated melanoma cells (DCCs) before and during metastatic colony formation and to study their interplay with local immune cells. Transcriptome analysis of DCCs identified activation of DCC-derived extracellular vesicle (EVs) production during metastatic colony formation. This was paralleled by CD8 T cell exhaustion, strongly suggesting a fundamental role of EVs in DCC-niche communication. We hypothesize that metastatic colony formation is driven by DCC-derived EVs, which (i) modulate phenotype and function of surrounding immune cells, (ii) provide growth support to yet pre-colonizing DCC-clones and (iii) whose production is activated by oncogenic pathways. The goal of the project is to identify and mechanistically dissect the role of molecular constituents of DCC-derived EVs and oncogenic pathways involved therein. We expect this knowledge to be fundamental for the understanding of early metastatic organ colonization in human melanoma with obvious impact for development of effective adjuvant therapies.

See also: https://www.experimentelle-medizin.de/en/research#

Project leader:
Claus Hellerbrand 
Institute of Biochemistry, 
FAU Erlangen-Nürnberg

The liver is a highly metastasis-permissive organ. The molecular mechanisms that render the liver such hospitable to disseminated tumour cells are widely elusive. We found that the attractiveness of the liver for metastasizing melanoma cells is further enhanced by hepatic steatosis. As potential steatosis-associated soiI factors we identified Bone Morphogenetic Protein 8B (BMP8B) and BMP-binding endothelial regulator (BMPER) as critical mediators of liver colonisation by disseminated cancer cells. The general goal of this project is to characterise the impact of hepatic steatosis on hepatic metastasis to identify novel therapeutic targets. We will also test whether identified factors affect colonisation of non-steatotic liver tissue as well as other metastatic niches, where they may be less abundant but still effective. Initially, we will focus on the characterisation of the role of BMP8B and BMPER in hepatic metastasis with melanoma as model tumour. Subsequently, the analysis will be expanded to further steatosis related factors and other types of cancer.

Project leaders:
Peter Dietrich 
Department of Medicine 1, 
FAU Erlangen-Nürnberg

Anja Bosserhoff 
Institute of Biochemistry, 
FAU Erlangen-Nürnberg

Liver organotropism of disseminated cancer cells is a hallmark of diverse cancer types including breast cancer, colon cancer, pancreatic cancer and melanoma. Likewise, the emergence of liver metastasis strongly contributes to the poor prognosis of these cancers. According to the "seed and soil" theory of metastasis, molecular cross-talk between cancer cells and non-tumourous parenchyma-derived cells underlies (liver) colonisation. Neuropeptide Y (Npy) and its G-protein coupled receptors represent a highly conserved system, which was shown to be involved in diverse mechanisms including cell migration and extravasation. Our previous work and unpublished data reveal strong chemotactic effects of liver- and sympathetic-nerve-derived neuropeptide Y (Npy) on disseminated cancer cells that express Npy-receptors. Moreover, TGFβ-induced EMT resulted in upregulation of Npy-receptors in cancer cells. TGFβ further promoted strong Npy-expression by liver cells. We hypothesize that Npy/Npy-receptor cross-talk drives homing, nerve infiltration and liver colonisation by disseminated cancer cells. In this project, we aim at characterising the Npy/Npy-receptor cross-talk between the liver metastatic niche and disseminated cancer cells applying in vitro and in vivo model systems as well as analysing patient-derived samples. Moreover, the Npy-dependent transcriptome and signaling pathways of disseminated cancer cell lines as well as the influence of the Npy-system on TGFβ- and EMT-induced gene signatures will be characterised. Furthermore, evaluation of a potential therapeutic targetability of newly revealed pathways driving Npy-mediated metastasis will be addressed.

Project leaders:
Armin Braun
Fraunhofer Institute for Toxicology and 
Experimental Medicine (ITEM),
Hannover

Frank Sonntag
Fraunhofer Institute for Material and Beam Technology, Dresden

Christian Werno
Fraunhofer ITEM-R, Personalized 
Tumour Therapy, Regensburg

To investigate early metastases and to test adjuvant therapies in presence of autologous immune cells novel preclinical immune competent in vitro models based on patient derived DCCs are needed. In project B13 we will therefore generate new LN-derived DCC organoid models from breast, colorectal and pancreatic cancer patients. To study colonization in a more complex and representative microenvironment we will use Precision Cut Tissue Slices from the main metastatic sites lung, liver and lymph nodes spiked with DCCs and immune cells from the same patients. To enable a prolonged cultivation of tissue slices and cocultures of DCCs in tissue preparations, we will develop new microfluidic systems. Thereby, we will establish a model of metastatic niches in vitro allowing to investigate mechanisms for colonization of DCCs in different organs, to unravel functions of different immune cells within this process and to test pharmaceutical interventions preventing colonization.

Project leaders:
Tobias Bäuerle
Institute of Radiology, Preclinical Imaging Platform Erlangen (PIPE), 
FAU Erlangen-Nürnberg

Thomas Wittenberg
Fraunhofer Institute for Integrated 
Circuits, Department of Informatics, 
Computer Graphics, 
FAU Erlangen-Nürnberg

Early processes of metastatic disease including colonization and inter¬ac¬tion of tumor cells with the microenvironment may be captured non-invasively in appropriate animal models using multimodal imaging strategies. Thereby, complementary information from high resolution magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), ultrasound (US) and optical imaging (OI) can be derived to determine early changes in the organ stroma on the morphological, func¬tional and molecular level. Most importantly, the data derived from the respective techniques have to be considered as complementary. Thereby, MRI offers a particularly high soft tissue contrast (e.g. visceral organs, but also bone marrow), while CT allows assessment of high contrast structures (e.g. bone), with spatial resolutions in the micrometer range, respectively. Functional parameters, e.g. associated with blood volume, vessel permeability or cellularity that are often altered in early metastasis can be calculated from techniques such as dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DWI). In particular MRI thus integrates morphologic and quantitative functional data in high spatial and temporal resolution. Finally, PET offers the acquisition of metabolic (e.g. [18F]-fluorodeoxyglucose, [18F]-FDG, [18F]-fluoride, [18F]-F) or molecular information (direct labelling of target molecules in metastasis, e.g. integrins or chemokine receptors), relevant for detection and follow-up of pathophysiologic processes in metastasis. Ultrasound has the advantage of real time imaging (high temporal resolution) combined with excellent soft tissue contrast, which is covering the whole range from morphologic, functional and molecular imaging. Finally, optical imaging is highly specific and sensitive to optical probes for bioluminescence and fluorescence (e.g. red or green fluorescent proteins) detecting changes on the cellular level.

Project leaders:
Fulvia Ferrazzi 
Institute of Pathology, 
FAU Erlangen-Nürnberg

Rainer Spang
Institute for Functional Genomics, 
University of Regensburg

The core project Z01 will support the TRR 305 projects with the generation, analysis and handling of large datasets by data management, data sharing, bioinformatics, imaging and image analysis. We will allow effective data sharing across projects with an intuitive web-browser application and eventually make the joint data resources of the CRC publicly accessible with appropriate cross-links between individual data sets. Furthermore, we will support all experimental CRC projects with expertise in the design of OMICS experiments, in the computational management and statistical analysis of the resulting data, and in the visualization and interpretation of the results. In addition, we will deliver advanced imaging infrastructures and tailored solutions for imaging of metastasis, as well as develop novel high-end image processing solutions for the TRR 305 members, including automated image analysis technologies.

Project leaders:
Katja Evert
Institute of Pathology, 
University of Regensburg

Peter Fasching
Department of Gynecology and 
Obstetrics, University Hospital Erlangen

Arndt Hartmann
Institute of Pathology, 
FAU Erlangen-Nürnberg

Christoph Klein
Experimental Medicine and Therapy 
Research, University of Regensburg

The clinical-pathological core Z02 will establish a platform that serves as a unique resource to test, validate, and specify research questions addressed in the various subprojects and the TRR 305 in general. For this, Z02 will establish and provide two distinct resources: First, a sample repository addressing the needs of the TRR 305 projects and second, access and targeted exploitation of the prospective molecular registry study PRAEGNANT. The sample repository will comprise a clinical infrastructure for targeted post-mortem autopsy studies, logistics for high-quality targeted post-mortem sampling procedures and a platform to track prospectively and longitudinally disease courses to address questions of cellular and molecular cancer evolution. In addition, we will utilize the availability of samples of patients with metastasized breast cancer gathered during the prospective molecular registry study PRAEGNANT.