Functional Genome Analysis  (B070)
Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580
D-69120 Heidelberg, Germany.
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  Functional Tumour Analyses  /  Pancreatic Cancer..
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Pancreatic Cancer

Melanoma
Other Cancers
  - Novel therapy by drug-repositioning
  - Serum-based diagnosis: proteins
  - Signatures of tumour-specific immune
  - Identification of tumour suppressors
  - Microenvironmental communication
  - Serum-based diagnosis: microRNAs
  - Melanoma tumour-niche formation 
  - Identification of cancer stem cell genes
  - Influence of peritumoral tissue
  - microRNA-based processes
  - Improving the efficiacy of immunotherapy
 
  - Early promotion of PDAC progression




Archive

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Pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the currently most deadly cancer. Mortality is close to incidence. Only about 5% of all patients survive longer than five years and the average survival period after diagnosis is about five months. Surgical resection represents still the best curative treatment approach for pancreatic cancer. However, it can only be applied to 10% to 20% of patients. PDAC is currently the fourth and seventh most common cause of cancer-related death in the Western world (Europe and the USA) and China, respectively, although ranked only tenth in incidence. The numbers are continuously rising, however, while declining for many other tumour entities. In 2030, PDAC is expected to be the second most cause of cancer-related death in the Western world, surpassing colorectal and breast cancer.
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Joining forces with leading groups in basic and clinical pancreatic cancer research, we study various molecular aspects in order to improve the basic understanding of PDAC tumour biology and pathology. To this end, we look in much detail at the communication between different cell types within the tumour microenvironment, for example, with a special focus on proteins. All this is complemented by studies on the functional consequences of the observed molecular changes.
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Taking advantage of the gained knowledge, we are aiming at establishing novel approaches for early diagnosis, disease prognosis and risk stratification of pancreatic cancer. To this end, we pursue particularly non-invasive liquid biopsy processes based on blood samples. Applying and combining different analysis forms, molecular signatures at various levels are defined that could enable accurate diagnosis.
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Also, we are active in identifying new therapeutic routes of high potential so as to improve on the current prognosis by means of innovative therapeutic strategies. One possible therapeutic option is at a stage that requires a clinical trial as the next step in the evaluation of its clinical utility.
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All this is done in several collaborations with partners worldwide. We have participated repeatedly in international and national consortia that covered various aspects of pancreatic cancer research. Locally, we have a strong and continuous cooperation with the European Pancreas Center at the Surgery Department of the Heidelberg University Clinics.

picture of a pancreatic tumour cell
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Image of a pancreatic cancer cell.
DNA in the nucleus is labelled blue; red signals show the cytoskeleton.

  







Bakadlag et al. (2019) Expert Opin. Ther. Tar. 23, 365-367. pdf icon
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Pausch et al. (2018) Pancreas 47, 561-567. pdf icon
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Throm et al. (2018) Oncotarget 9, 11734-11751. pdf icon
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Kaistha et al. (2017) Oncotarget 8, 66215-66225. pdf icon
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Mustafa et al. (2017) Oncotarget 8, 11963-11976.  pdf icon
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Novel Therapy Option:
DRD2 is critical for pancreatic cancer and promises pharmacological therapy by already established antagonists
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Incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) are almost equivalent, urging for the development of better therapeutic strategies. We investigated novel potential therapeutic targets for PDAC by performing global gene expression profiling in 195 PDAC and 41 normal pancreatic tissue samples. Superimposing the pathway context and interaction networks of aberrantly expressed genes, we identified factors with central roles in PDAC pathways. Next, tissue microarray analysis was used to verify the expression of the candidate targets in an independent set of 152 samples comprising 40 normal pancreatic tissues, 63 PDAC sections and 49 samples of chronic pancreatitis.

We identified dopamine receptor D2 (DRD2) as a key modulator of cancer pathways in PDAC. DRD2 up-regulation at the protein level was validated in a large independent sample cohort. Most importantly, we found that blockade of DRD2, through RNAi or pharmacological inhibition using FDA-approved antagonists, such as
Haloperidol, hampers the proliferative and invasive capacities of pancreatic cancer cells in vitro and in vivo while modulating cAMP and endoplasmic reticulum stress pathways. Our findings demonstrate that inhibiting DRD2 represents a novel therapeutic approach for PDAC. Given that DRD2 antagonists are currently routinely used for the management of schizophrenia or other mental diseases, a drug-repositioning strategy could facilitate the clinical use of these agents for treating pancreatic cancer.

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Bakadlag et al. (2019) Expert Opin. Ther. Tar. 23, 365-367.  pdf icon
Jandaghi et al. (2016) Gastroenterology 151, 1218-1231.  pdf icon
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Protein-based microenvironmental communication in pancreatic ductal adenocarcinoma

We study the communication that is ongoing between the various cell types in a tumour tissue, such as activated pancreatic stellate cells and macrophages next to the tumour cells of pancreatic ductal adenocarcinoma (PDAC). In particular, we analyse their secretomes. Also, the effect on other cells is looked at. Cells are grown in the different secretomes and are analysed with respect to molecular and functional consequences. A graphical overview of the process is shown to the right, presenting analyses done on pancreatic stellate cells and the effect of their secretome on tumour cells. Early, already published results are on the interaction of stellate and tumour cells as well as the analysis of the tumour cell secretome.

Next to bilateral interactions, we have developed a system that allows to study the interaction of several cell types simultaneously, basically creating an environment under controlled conditions that represents the cell composition of tumour tissue.
 
Marzoq et al. (2019) Sci. Rep. 9, 5303. pdf icon
Mustafa et al. (2017) Oncotarget 8, 11963-11976.  pdf icon



Figure legend: Scheme of a typical overall experimental set-up of studying bilaterally the interaction of two cell types: here, pancreatic stellate and tumour cells. First, the protein content of the secretome of activated pancreatic stellate cells (PSCs) was analysed and predictions were made about the functional consequences, which the secreted proteins would have in recipient tumour cells. Second, tumour cells were grown in media conditioned with secretome. The intracellular proteome was studied and used for functional predictions. The predictions from secretome and intracellular proteome analyses were compared and validated by investigating the actual functional variations observed and by identifying relevant regulative factors.

 
Scheme of the approach taken
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Transcript variations in the wider peritumoral tissue environment of pancreatic cancer

Transcriptional profiling was performed on 452 RNA preparations isolated from various types of pancreatic tissue from tumour patients and healthy donors, with a particular focus on peritumoral samples. Pancreatic ductal adenocarcinomas (PDAC) and cystic tumours exhibited rather similar transcript patterns; in both cases, about 5000 genes were differentially transcribed (see figure below). In addition, all changes were identical in direction, up or down (see figure, right panel). Not a single gene out of 5000 was found to be up-regulated in one tumour but down-regulated in the other.
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PDAC and cystic tumours were most different in the nontumorous tissues surrounding them. As a matter of fact, the environment of cystic tumours was transcriptionally nearly identical to normal pancreas tissue. In contrast, the tissue surrounding PDAC-tumours behaved a lot like the tumour itself - indicating some kind of field defect - while showing far less molecular resemblance to both chronic pancreatitis and healthy tissue. This suggests that major pathogenic differences between cystic and ductal tumours may be due to their cellular environment rather than the few variations within the tumours.
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Functionally, a strikingly large number of autophagyrelated transcripts was changed in both PDAC and its peritumoral tissue, but not in other pancreatic tumours. A transcription signature of 15 autophagyrelated genes was established that permits a prognosis of survival with high accuracy and indicates the role of autophagy in tumour biology.
 
Bauer et al. (2018) Int. J. Cancer 142, 1010-1021. pdf icon



 
Figure legend: Tissue specificity of mRNA level variations. For each tissue type, the number of mRNAs is shown that were significantly differentially expressed in comparison to normal pancreas tissue (N). The numbers in overlap regions stand for genes, regulated similarly in the relevant tissues. Left panel: Results are presented for PDAC, the related peritumoral tissue (N_PDAC) and chronic pancreatitis (CP), marked in red, green and yellow, respectively. Central panel: The panel presents the same information for cystic tumours (TC; brown), the related peritumoral tissue (N_CT; blue) and again chronic pancreatitis (CP; yellow). R ight panel: Correlation in the direction of variation observed for CT versus N in comparison to PDAC versus N. Both axes represent the score shown above the panels, thus focussing on the most significant variations (shown in blue). Grey dots, mostly close to the centroid, represent insignificant changes.
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Early epigenetic down-regulation of microRNA-192 expression promotes pancreatic cancer progression logo NGFN
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Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. We identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis (CP), the latter of which is a major risk factor for development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition (EMT). Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy.
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Figure legend. Two cell lines, which express miR-192 at high level (CFPAC-1) or low level (MIAPaCa-2) were transfected with constructs that suppressed or increased miR-192 expression, respectively. Xenografted into mice, strong effects on tumour growth were observed.
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Botla et al. (2016) Cancer Res. 76, 4149-4159. 
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