Medical University of Vienna
Institute of Cancer Research (Principle Investigator)
Department of Medicine I
1090 Vienna, Austria
Phone: +43 1 40160-57571
We are interested to understand the molecular basis of colorectal cancer. We focus on JAK-STAT signaling and protective molecules such as protocadherins and investigate their functions in colitis, intestinal stem cell differentiation, mucosal regeneration and neoplastic transformation. A particular focus is the role of JAK-STAT signaling in the tumor microenvironment. For our experiments, we use experimental tools for deletion of individual JAK-STAT components in intestinal epithelial cells and immune cells of mice.
Mucosal implantation models for investigation of colon cancer immune escape. Recently, we discovered a paneth-like cell type that depends on Stat1 and expresses the immune checkpoint molecule Ido1. Loss of these cells in Stat1-deficient intestinal adenomas had profound effects on the stromal immune cell composition. We hypothesize that metabolic products of these cells shape the stroma in a way that makes tumors resistant to immunotherapy (Svinka et al., manuscript in preparation). We intend to prove the importance of these cells in immune escape by mucosal implantation of genetically manipulated patient-derived CRC organoids (PDOs) into MISTRG-IL6-IL15-HLA-A2 mice, which represent the latest development of immune-humanized mice (with DHB). PDO cultures and the mucosal implantation technique will be established in collaboration with GE and MS, respectively. The mucosal location of human tumors and the stromal infiltration with innate and adaptive human immune cells will allow us to test PD-1-, NK cell- or myeloid cell-based immunotherapies and anti-metastatic therapies that rely on an intact immune system in mice1,2. Using CRISPR/Cas9, we will delete Stat1 and Ido1 and assess the effects on growth and progression of PDOs3 in a humanized immune microenvironment (with LK). In addition to the translational value of our implantation model and the putative discovery of new targets for immunosensitization of colon tumors, our research represents a major conceptual advance in mucosal immunity and mechanisms of cancer immune escape.
- Herndler-Brandstetter, D.; Shan, L.; Yao, Y.; Stecher, C.; Plajer, V.; Lietzenmayer, M.; Strowig, T.; Zoete, M. R. de; Palm, N. W.; Chen, J.; et al. Humanized Mouse Model Supports Development, Function, and Tissue Residency of Human Natural Killer Cells. Proc. Natl. Acad. Sci. 2017, 114 (45), E9626–E9634. doi.org/10.1073/pnas.1705301114.
- Ring, N. G.; Herndler-Brandstetter, D.; Weiskopf, K.; Shan, L.; Volkmer, J.-P.; George, B. M.; Lietzenmayer, M.; McKenna, K. M.; Naik, T. J.; McCarty, A.; et al. Anti-SIRPα Antibody Immunotherapy Enhances Neutrophil and Macrophage Antitumor Activity. Proc. Natl. Acad. Sci. 2017, 114 (49), E10578–E10585. doi.org/10.1073/pnas.1710877114.
- Schwank, G.; Koo, B.-K.; Sasselli, V.; Dekkers, J. F.; Heo, I.; Demircan, T.; Sasaki, N.; Boymans, S.; Cuppen, E.; van der Ent, C. K.; et al. Functional Repair of CFTR by CRISPR/Cas9 in Intestinal Stem Cell Organoids of Cystic Fibrosis Patients. Cell Stem Cell 2013, 13 (6), 653–658. doi.org/10.1016/j.stem.2013.11.002.