CeMM Adjunct Principal Investigator

Georg Busslinger
Gastrointestinal Biology

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Biosketch
Selected Papers

Our group is interested in the epithelial cell biology of human gastrointestinal organs, in particular the esophagus, stomach and small intestine. These organs have specific functions that act in a coordinated manner to facilitate nutrient uptake. The esophagus transports the ingested food to the stomach. The stomach sterilizes the food content by generating a harsh acidic environment to eliminate undesirable bacteria and starts to pre-digest its content. The small intestine is responsible for nutrient digestion and absorption. These diverse tasks are executed by highly specialized epithelial cell types in the different organs, which are characterized by a fast turnover, as they are renewed every few days during normal homeostasis. Impaired gastrointestinal homeostasis is associated with a wide variety of diseases, which occur quite frequently in the human population. Chronic inflammation can lead to esophagitis, Barrett’s esophagus, gastritis or Crohn’s disease, which may ultimately lead to cancer. In particular, esophageal and gastric cancers are quite aggressive as treatment options are so far limited.

Gastrointestinal organoids

The molecular functions of the distinct epithelial cell types and corresponding tumor cells in gastrointestinal organs have largely been investigated in animal models or more recently by descriptive single-cell studies in humans. The functional analysis of human epithelial cell types has been revolutionized by the advent of organoid cultures that can be established from adult epithelial stem cells and propagated indefinitely without immortalization. Human gastrointestinal organoids, which can be derived from healthy tissue or tumor biopsies, maintain the epithelial cell complexity, architecture and differentiation potential. Together with other recent technological advances such as single-cell genomics and CRISPR/Cas9-mediated genome editing, it is now possible to characterize the function of human gastrointestinal cell types and tumors in an unprecedented depth.

Function of gastrointestinal epithelial cell types

By single-cell analysis, we have recently provided novel insight into the cellular composition and gene expression patterns of the distinct epithelial cell types in the human esophagus, stomach and duodenum. Future research of our group will focus on the functional analysis of selected cell types such as the acid-producing parietal cells and hormone-expressing enteroendocrine cells of the human stomach as well as the newly identified BCHE cells of the human duodenum. For this, we will insert fluorescent marker genes into a cell type-specific gene for subsequent identification and isolation of the differentiated cell type in the respective organoid cultures. These differentiated cell types will be studied with regard to their behavior in response to extracellular signals, their mode of action and their potential contribution to disease. We will also investigate the response of the gastric and duodenal organoids to environmental cues provided by nutrients and the microbiome that may affect cell behaviour and contribute to cancerogenic processes. All projects heavily rely on organoid cultures, genome editing and sequencing technologies.

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Biosketch

Georg Busslinger studied molecular biology first at the University Vienna and obtained his master’s degree at the ETH Zurich (Switzerland). Before initiating his PhD, he investigated the epigenetic regulation of the interferon response for one year in the laboratory of Alexander Tarakhovsky at the Rockefeller University in New York (USA). He subsequently joined the group of Jan-Michael Peters at the Research Institute of Molecular Pathology (IMP) in Vienna for his PhD studies and investigated the molecular mechanisms that control the localization of cohesin in the mammalian genome of non-proliferating cells. For his postdoctoral study, he joined the laboratory of Hans Clevers at the Hubrecht Institute in Utrecht (The Netherlands), where he became an expert in the field of organoid biology. He characterized the human gastrointestinal epithelia of the esophagus, stomach and duodenum at single-cell resolution, which resulted in a molecular definition of the different cell types of these organs, as well as in the identification of rare cell populations and of a novel hormone produced by enterochromaffin-like cells. Additionally, he investigated the cellular and molecular aspects of different stages of Barrett’s esophagus, a common pre-malignant state of esophageal adenocarcinoma. Together with doctors of the UMC Utrecht, he initiated a research study to investigate the potential of in vitro esophageal and gastric tumor organoid cultures for predicting the patient response in vivo to chemotherapeutic treatments.

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Selected Papers

Beumer J., Puschhof J., Bauza-Martinez J., Martinez-Silgado A., Elmentaite R., James K.R., Ross A., Hendriks D., Artegiani B., Busslinger G.A., Ponsioen B., Andersson-Rolf A.,Kretzschmar K., Geurts M.H., Bar-Ephraim Y.E., Pleguezuelos Manzano C., Post Y., van der Linden F., Lopez Iglesias C., van de Wetering W.J., van der Linden R., Peters P.J., Heck A.J.R., Goedhart J., Snippert H., Zilbauer M., Teichmann S.A., Wu W. and Clevers H. (2020) High Resolution mRNA and secretome atlas of human enteroendocrine cells. Cell 181, 1-16 (abstract)

Busslinger G.A., Lissendorp F., Franken I., van Hillegersberg R., Ruurda J., Clevers H., de Maat M. (2020) The potential and challenges of patient-derived organoids in guiding the multimodality treatment of upper gastrointestinal malignancies. Open Biol. 10: 190274 (abstract)

Holzmann J., Politi A.Z., Nagasaka K., Hantsche-Grininger M., Walther N., Koch B., Fuchs J., Dürnberger G., Tang W., Ladurner R., Stocsits R.R., Busslinger G.A., Novak B., Mechtler K., Davidson I.F., Ellenberg J., Peters J.M. (2019) Absolute quantification of cohesin, CTCF and their regulators in human cells. Elife 8: e46269 (abstract)

Busslinger G.A., Stocsits R.R., van der Lelij P., Axelsson E., Tedeschi, A., Galjart N., Peters, J.-M. (2017) Cohesin is positioned in mammalian genomes by transcription, CTCF and Wapl. Nature 544, 503 -507 (abstract)

Ladurner R, Kreidl E, Ivanov M.P., Ekker H, Idarraga-Amado M.H., Busslinger G.A., Wutz G., Cisneros D.A., Peters J.M. (2016) Sororin actively maintans sister chromatid cohesion. EMBO J 25, 635-653 (abstract)