In the Hebrok lab we leverage human stem cell and organoid technology to investigate pancreas development and disease-related mechanisms underlying diabetes and pancreatic cancer.
In the Hebrok lab we utilize state-of-the-art technologies such as genetic editing, microfluidics, ‘OMICS’ and in vivo approaches, to faithfully generate, build, modify and functionally characterize organoids of the pancreas from human pluripotent stem cells. The pancreas is of great medical interest as it provides vital functions and is afflicted by two prominent diseases: diabetes and pancreatic cancer. We aim to use our pancreatic organoids to gain novel insights into the biology of this organ, to query disease-related pathological processes, and to develop new diagnostic tools and therapies.
The pancreas harbors two distinct compartments: the exocrine compartment whose cells secrete and transport digestive enzymes into the gut, and the endocrine compartment whose cells produce hormones essential for the regulation of blood sugar levels. Using exocrine and endocrine organoids derived from human stem cells we work on further exploring the mechanisms underlying pancreatic cancer formation. We are primarily interested in defining the origin and developmental steps of pancreatic neoplasms such as ductal adenocarcinomas (PDA), one of the most lethal cancers in humans, as well as neuroendocrine tumors (PanNETs) that turn aggressive upon spreading. We investigate how the deregulation of cellular activities, including epigenetic and transcriptional regulators and signaling pathways, drives the transformation of healthy pancreatic cells into tumors. Not only do we focus on these cell-intrinsic processes, we are also interested in defining interactions of the pre-cancerous and cancerous cells with other surrounding cell types, such as fibroblasts, and how they influence cancer development. The overarching goal is to define targetable inflection points when normal cells turn cancerous that can be exploited for the development of novel therapeutics.
In the context of diabetes, we are interested in improving the generation of functional insulin-producing cells and making stem-cell derived islet clusters more resilient for transplantation purposes. The long-term goal is to develop new avenues for cell replacement therapy in patients with diabetes. Finally, we would like to understand how the endocrine cells influence the development of PDA. Type 2 diabetes, a form that is mainly caused by poor lifestyle and insulin resistance, is a known risk factor and often precedes PDA. The mechanisms of this tumor-promoting action are still largely unknown yet may provide novel opportunities for early diagnosis and therapeutic intervention.
The Hebrok lab has strong collaborations with research groups at Helmholtz Munich, Klinikum rechts der Isar der TUM, TUM Center for Functional Protein Assemblies, TUM Institute for Biomedical Engineering, Ludwig Maximilian University of Munich (LMU) and University of California San Francisco. Our second lab location is at the Institute for Diabetes and Organoid Technology at Helmholtz Munich.
Prof. Dr. Matthias Hebrok (Principal Investigator)
Dr. Laura Leonhardt (Scientific Strategist/Project Manager)
Dr. Kai Duan (Postdoc)
Rachita Gupta, B.Sc. (Master student)
Lars-Henrik Joost, M.Sc. (PhD student)
Diana Lochner (Administrative Assistant)
Dr. Hasna Maachi (Postdoc)
Francisco Martín Hinojosa, M.Sc. (Technician)
Dr. Jia Mei (Postdoc)
Marierose Mina, M.Sc. (PhD student)
Hannes Rolbieski (Lab Manager)
Natalie Scherf, B.Sc. (Master student)
Sabina Szüts (Technician)
Damla Taskin, M.Sc. (PhD student)
Merve Yigin, M.Sc. (PhD student)
Maria Zacherl (Technician)
Sox9 regulates alternative splicing and pancreatic beta cell function. Puri, S., Maachi, H., Nair, G., Russ, H. A., Chen, R., Pulimeno, P., Cutts, Z., Ntranos, V., and M. Hebrok. Nature Communications (2024)
Replenishable prevascularized cell encapsulation devices increase graft survival and function in the subcutaneous space. Chendke, G. S., Kharbikar, B. N., Ashe, S., Faleo, G., Sneddon, J. B., Tang, Q., Hebrok, M. and T. A. Desai. Bioengineering & Translational Medicine (2023)
Loss of ZNF148 enhances insulin secretion in human pancreatic ß cell. de Klerk, E., Emfinger, C. H., Keller, M. P., Xiao, Y., Berrios, D.I., Loconte, V., Ekman, A. A., White, K. L., Cardone, R. L., Kibbey, R. G., Attie, A. D., and M. Hebrok. JCI Insight (2023)
Development of a scalable method to isolate subsets of stem cell-derived pancreatic islet cells. Parent, A. V.*, Ashe S., Nair, G. G., Li, M-L., Chavez, J., Liu, J. S., Zhong, Y., Streeter, P. R., and M. Hebrok*. Stem Cell Reports (2022) *co-corresponding authors.
Selective deletion of human leukocyte antigens protects stem cell-derived islets from immune rejection. Parent, A. V.*, Faleo, G., Jessica Chavez, J., Saxton, M., Berrios, D.I., Kerper, N.R., Qizhi Tang, Q., and M. Hebrok*. Cell Reports (2021) *co-corresponding authors.
Loss of the transcription factor MAFB limits β-cell derivation from human PSCs. Russell, R., Carnese, P. P., Hennings, T. G., Walker, E. M., Russ, H. A., Liu, J. S., Giacometti, S., Stein, S., and M. Hebrok. Nature Communications (2020)
Recapitulating endocrine cell clustering in culture promotes maturation of human stem cell-derived beta cells. Nair, G. G., Liu, J., Russ, H. A., Tran, S., Saxton, M., Chen, R., Juang, C., Li, M. L., Nguyen V.Q., Giacometti S., Puri, S., Xing, Y., Wang, Y., Szot, G., Oberholzer, J., Bhushan, A., and M. Hebrok. Nature Cell Biology (2019)
The BRG1/SOX9 axis is critical for acinar cell–derived pancreatic tumorigenesis. Tsuda, M., Fukuda, A., Roy, N., Hiramatsu, Y., Leonhardt, L., Kakiuchi, N., Hoyer, K., Ogawa, S., Goto, N., Ikuta, K., Kimura, Y., Matsumoto, Y., Takada, Y., Yoshioka, T., Maruno, T., Yamaga, Y., Kim, G. E., Akiyama, H., Ogawa, S., Wright, C. V., Saur, D., Takaori, K., Uemoto, S., Hebrok, M., Chiba, T., and H. Seno. Journal of Clinical Investigation (2018)
Replication confers ß cell immaturity. Puri, S., Roy, N., Russ, H. A., Leonhardt, L., French, E. K.,Roy, R., Bengsston, H., Scott, D. K., Stewart, A. F., and M. Hebrok. Nature Communications (2018)
PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance. Roy, N., Takeuchi, K. K., Ruggeri, J. M., Bailey, P., Chang, D., Li, J., Leonhardt, L., Puri, S., Song, Y., Ljungman, M., Malik, S., Wright, C. V. E., Dawson, D. W., Biankin, A., Hebrok, M.* and H. C. Crawford*. Genes & Development (2016) *co-corresponding authors.
Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. Russ, H. A., Parent, A. V., Ringler, J. J., Hennings, T. G., Nair, G. G., Shveygert, M., Guo, G., Puri, S., Haataja, L., Cirulli, V., Blelloch, R.,Szot, G., Arvan, P. and M. Hebrok. Embo J. (2015)
Brg1 promotes both tumor suppressive and oncogenic activities at distinct stages of pancreatic cancer formation. Roy, N.*, Malik, M.*, Villanueva, K. E., Urano, A., Lu, X., von Figura, G., Seeley, S. E., Collisson, E. A., Dawson, D. W., and M. Hebrok. Genes & Development (2015) *equal contribution
Full publication list: PubMed, Google Scholar
Bayerisches Spitzenprofessurenprogramm (Bavarian Distinguished Professorship)
National Institutes of Health (NIH)
Juvenile Diabetes Research Foundation (JDRF)
Prof. Dr. Matthias Hebrok
Chair for Applied Stem Cell and Organoid Systems
matthias.hebrok(at)tum.de
Admin:
Antonie Wöckel
+49 (89) 289 - 12813
antonie.wöckel(at)tum.de
Lab address:
Center for Functional Protein Assemblies (CPA)
Ernst-Otto-Fischer-Str. 8
85748 Garching b. München