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Two new research grants by Berliner Krebsgesellschaft
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The Berliner Krebsgesellschaft will fund two very interesting research projects by Dr. Linda Feldbrügge and Dr. Karl Hillebrandt in collaboration with Dr. Björn Papke.

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„Purinergic immune regulation in peritoneal metastases of gastric cancer via CD39 and ENTPD3 – target for a novel immune Checkpoint inhibition?“ – PI: Dr. Linda Feldbrügge

Peritoneal metastasis, especially derived from gastric cancer (GC), has a poor prognosis with a median survival of only months. Treatment is usually confined to palliative systemic chemotherapy, complemented individually by checkpoint inhibitors that block PD1-signaling. Innovative therapies combining surgery with local drug application such as hyperthermic intraperitoneal chemotherapy (HIPEC) or pressurized intraperitoneal aerosol chemotherapy (PIPAC) are still pending confirmation in clinical trials. Purinergic signaling, which involves ATP hydrolysis and generation of adenosine, regulated through CD39 (ENTPD1) and related enzymes, has been recognized as a critical immunoregulatory pathway in the tumor microenvironment (TME). The objective of the current project is to characterize the immune environment in the unique setting of peritoneal metastasis of gastric cancer with a focus on ectonucleotidases CD39 and ENTPD3 on T cells, macrophages and MDSC as well as mechanisms of ectonucleotidase-mediated immune regulation in tumor associated macrophages in vitro. As a high-volume center for surgical therapy of peritoneal malignancies and with years of experience in ectonucleotidase research, we aim to advance the understanding of peritoneal metastasis and contribute to improving treatment options for our patients.

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"The influence of decellularised tumour matrix heterogeneity in relation to KRAS/MAPK inhibition of in vitro colorectal liver metastases." PI: Dr. Karl Hillebrandt and Dr. Björn Papke (Dept. of Pathology)

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, with approximately 900,000 annual deaths. 30-50% of patients develop colorectal liver metastases (CRLM) during their disease. More than 50% of these tumors have mutations in the KRAS oncogene, making them usually poorly treatable. Despite multimodal therapy concepts have improved the outcome of these patients, a large proportion of patients suffer a recurrence of their disease. For better therapeutic concepts, we need to better understand the tumor biology and metastatic mechanisms of these diseases. In vitro models, such as two-dimensional cell culture, are primarily used for this purpose. These models can only reflect the physiological complexity to a limited extent. Recently, it was shown that the use of organ-specific and tumor-specific extracellular matrix (ECM) has an impact on the behavior of human CRC cell lines. Culture of cell lines with decellularized matrix resulted in cells adopting a metastatic cell state and forming significantly more metastases in a mouse model than cells cultured on plastic or collagen. The goal of our project is to study the growth (with and without inhibition of the RAS/MAPK signaling pathway) of patient-derived tumor organoids growing on different decellularized metastatic matrices (dMM) and decellularized liver matrices (dLM). These studies of tumor matrix heterogeneity are essential to define which starting materials, for in vitro modeling of our three-dimensional tumor organoid culture, can be used to develop the most physiological, personalized dLM/dMM-based CRLM in vitro model possible. Based on these results, we plan to conduct small-scale therapy evaluations for personalized tumor therapy using our in vitro dLM/dMM-based CRLM in the near future.

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BIH Charité Clinician Scientist Symposium in Honor and Memory of Duška Dragun
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28 May 2021 - 29 May 2021
BIH Charité Clinician Scientist Symposium in Honor and Memory of Duška Dragun

The symposium is composed of several components: First and foremost, it will commemorate Prof. Duška Dragun, the former Director of the BIH Biomedical Innovation Academy (BIA) and Director of the BIH Charité Clinician Scientist Program, who passed away in December 2020, and will be joined by stakeholders from academia and science policy. In addition, there will be scientific sessions, which will form tandems of program fellows and invited speaker. During a digital certificate ceremony on the evening of 28 May 2021, some 50 alumni will be bid farewell. The event language is English.

When
28 and 29 May 2021
10:00 - 6:30 pm

How
Online Event (semi-digital)

Registration
To receive the login link please register here.
Advanced Clinician Scientists
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Priv.-Doz. Dr. Nathanael Raschzok and Priv.-Doz. Dr. Felix Krenzien successfully applied for the BIH Charité Advanced Clinician Scientist Pilot Programme (AdCSP) in a highly competitive process.

The BIH Charité AdCSP is designed as a career-phase-specific, sustainable funding programme that aims to closely interlink individual and institutional funding. The primary goal of the programme is to simultaneously incentivise the fellows and recognise the permissive academic culture of the respective clinics or institutes. Like the BIH Charité Clinician Scientist Programme (CSP) and the "Digital Clinician Scientist Programme" (DCSP), which has been additionally funded by the DFG since 2019, it is intended to be open to all clinical disciplines and to offer multiple networking opportunities for the funded fellows and participating clinics and institutes.

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Grant provided by the Berliner Krebsgesellschaft e.V.
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Dr. med. M. Felsenstein receives a grant provided by the Berliner Krebsgesellschaft e.V. for his project "Deciphering the molecular determinants of pancreatic duct dysplasia by analysis of single-cell transcriptomics (RNAseq) in precursor lesions".

Besides great advances in the molecular and genetic understanding of pancreatic duct adenocarcinoma (PDAC), this tumor entity remains particularly aggressive with dismal prognosis. Recent single-cell sequencing studies underline the eminent urgency to understand tumor heterogeneity in the setting of PDAC. More detailed knowledge about the molecular mechanisms of pancreatic cancer evolution, carcinogenesis and heterogeneity could direct ideas for earlier detection and more effective targeted therapies, also preventing disease recurrence. Future therapeutic approaches in precision medicine will likely focus on the disease relevant sub-populations, specifically driving cancer progression, dissemination and exerting tumor escape mechanisms. In-depth transcriptomic data of single carcinoma environmental cells and respective cell clusters may help to discover novel biomarkers, which can be clinically instrumented for earlier detection and putatively increase the fraction of patients, amenable to curatively intended therapies. This study aims to analyze sorted single cells of macro-dissected precursor and cancerous lesions of the pancreas by single nuclei RNA sequencing (snRNAseq). In this feasibility study, we will include 10 patients, who will undergo resection of the pancreas due to “worrisome” or malignant lesions. We will perform in-depth transcriptomic analysis of pancreatic dysplasia in order to broaden our understanding of the molecular mechanisms of pancreatic carcinogenesis.

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Notch Signaling Pathway in Pancreatobiliary Tumors
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The Notch signaling pathway plays an important role both in the development of the ductal systems of the pancreas and the bile ducts as well as in cancer development and progression. The aim of this study was to examine the expression of central proteins of the Notch signaling pathway in pancreatobiliary tumors and its influence on patient survival.

Materials and Methods: We compared the receptors (Notch1, Notch4), activating splicing factors (ADAM17), and target genes (HES1) of the Notch pathway and progenitor cell markers with relevance for the Notch signaling pathway (CD44, MSI1) between pancreatic adenocarcinomas (PDAC, n = 14), intrahepatic cholangiocarcinoma (iCC, n = 24), and extrahepatic cholangiocarcinoma (eCC, n = 22) cholangiocarcinomas.

A significant overexpression of almost all studied components of the Notch signaling pathway can be found in the tumor tissue, however, without a significant influence on patient survival. Therefore, further studies are warranted to draw conclusions on Notch pathway's relevance for patient survival.

The paper "Notch Signaling Pathway in Pancreatobiliary Tumors" is available via Medicina, 2021;57(2):105. Authors are Francesca Borlak, Anja Reutzel-Selke, Anja Schirmeier, Julia Gogolok, Ellen von Hoerschelmann, Igor M Sauer, Johann Pratschke, Marcus Bahra, and Rosa B Schmuck.
Karl Hillebrandt | Charité 3R Tandem project for early career researchers
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Together with Dr. Björn Papke (Molecular tumour pathology), Dr. Karl Hillebrandt was able to acquire funding for a "Tandem project for early career researchers" from the Charité 3R. The project is entitled "A personalised therapy approach implementing individually matched matrix-based in vitro colorectal liver metastases to reduce metastatic mouse models".
Although modern multimodal therapy strategies have improved the clinical outcome of patients with colorectal liver metastases (CRLM), the overall prognosis is still poor. To further improve treatment options for patients, it is necessary to develop and test new targeted therapeutic approaches. To date, mouse models have often been used to study metastatic colorectal cancer. However, the rate of successful translation of animal models into clinical trials is less than 8%, highlighting the urgent need for alternative models to study the biology of metastatic cancer. This project aims to develop a novel personalised extracellular matrix-based in vitro model of human CRLM. This model will be validated against existing data from patient-derived organoids and xenografts (histology, single cell RNA sequencing and targeted gene sequencing). After internal comparison of our in vitro CRLM with the original CRLM, we will translate it into a personalised drug screening platform to test drug response from standard therapy to novel inhibitor combinations.
Characterization of pancreatic and biliary cancer stem cells in patient-derived tissue
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Pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangio-carcinoma (eCC) represent two cancer entities with devastating prognoses. Despite recent progress in research and treatment, therapy remains challenging. Cancer stem cells (CSCs) have been shown to play an important role in metastasis and chemoresistance. Therefore, CSCs may play a promising role as a potential therapeutic target.
A total of 31 patients (23 PDAC, 8 eCC) were included in the study. CSCs were analyzed in a single-cell suspension of tumor samples via fluorescence-activated cell scanning (FACS) with a functional Hoechst 33342 staining as well as a cell surface marker staining of the CSC-panel (CD24, CD44 and EpCAM) and markers to identify fibroblasts, leukocytes and components of the notch signaling pathway. Furthermore, the potential presence of CSCs among primary cancer-associated fibroblasts (CAFs) was assessed using the same FACS-panel.
We showed that CSCs are present in patient-derived dissociated tumor tissue. The functional and surface marker profile of CSC-detection did in fact correlate. The amount of CSCs was significantly correlated with tumor characteristics such as a higher UICC stadium and nodal invasion. CSCs were not restricted to the epithelial cell fraction in tumor tissues, which has been verified in independent analysis of primary cell cultures of CAFs.
Our study confirms the in vivo presence of CSCs in PDAC and eCC, stating a clinical significance thereof and thus their plausibility as therapeutic targets. In addition, stem-like cells also seem to constitute a part of the CAFs.

"Characterization of Pancreatic and Biliary Cancer Stem Cells in Patient-derived Tissue" was published in Anticancer Research. Authors are J. Gogolok, E. Seidel, A. Strönisch, A. Reutzel-Selke, I.M. Sauer, J. Pratschke, M. Bahra, and R.B. Schmuck.
Two new BIH Charité Junior Clinician Scientists
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Dr. Karl Hillebrandt and Dr. Matthäus Felsenstein successfully applied for the BIH Charité Junior Clinician Scientist Program. Karl Hillebrandt will continue his work on human decellularized liver slices as 3D platform for in vitro models of cholangiocellular carcinoma. Matthäus Felsenstein focusses on derivation of normal pancreatic duct cells from human primary tissue and their stepwise genetic modification in vitro using CRISPR/Cas9 .

Congratulations!
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