Our lab is interested in the underlying mechanisms of adult tissue homeostasis and the early steps of tumorigenesis, the stage where adult stem cells acquire the first tumor-associated mutation(s) allowing them to outcompete their neighbors for growth. Using a combination of genetics tools, in vivo and in vitro models, and imaging techniques, we aim to understand how the homeostatic tissue regeneration is regulated and how tumorigenic mutations affect the balance of adult stem cells.
Our lab focuses on three aspects of adult stem cells with focus on the digestive tract organs as models:
- Adult stem cells in the stomach:
Our lab identified two types of adult stem cells in the stomach corpus glands: active-cycling isthmus stem cells (Han et al., CSC, 2019) and slow-cycling Troy+ stem cells (Stange and Koo et al., Cell, 2013). While we know the two pools of stem cells replenish different regions of the corpus glands in homeostasis, this property changes upon injury. Will similar changes occur with the introduction of oncogenic mutation? How will neighboring cells respond and what are the mechanisms driving these changes?
- Adult stem cell homeostasis in the intestine:
The proliferation and differentiation of adult stem cells are governed by various signaling networks which must be tightly regulated. One modulator of signaling pathways is a family of E3 ubiquitin ligases which conjugates ubiquitin to target proteins for degradation. RNF43;ZNRF3 and Mib1 have been shown to regulate Wnt and Notch activity in intestinal stem cells, respectively (Koo et al., PNAS, 2015; Koo et al., Nature, 2012; Koo et al., Gastroenterology, 2009). We are interested in how dysregulation of E3 ligases can lead to an alteration of balanced signaling network of adult stem cells which could drive tissue degeneration or tumorigenesis.
- Adult stem cells at the beginning of malignant transformation:
Using a novel variant of the Rosa-Confetti reporter allele (Red2cDNA) series, we will investigate the effect of oncogenic gene expression in initiating clonal expansion and early tumorigenesis. This system eables us to investigate the effect of oncogenic signals not only on the target cell but also on surrounding neighboring cells in the microenvironment.
Han, S., Fink, J., Jörg, DJ., Lee, E., Yum, MK., Chatzeli, L., Merker, SR., Josserand, M., Trendafilova, T., Andersson-Rolf, A., Dabrowska, C., Kim, H., Naumann, R., Lee, JH., Sasaki, N., Mort, RL., Basak, O., Clevers, H., Stange, DE., Philpott, A., Kim, JK., Simons, BD., Koo, BK. (2019). Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells. Cell Stem Cell.
Seidlitz, T., Chen, YT., Uhlemann, H., Schölch, S., Kochall, S., Merker, SR., Klimova, A., Hennig, A., Schweitzer, C., Pape, K., Baretton, GB., Welsch, T., Aust, DE., Weitz, J., Koo, BK., Stange, DE. (2019). Mouse Models of Human Gastric Cancer Subtypes With Stomach-Specific CreERT2-Mediated Pathway Alterations. Gastroenterology. 157(6):1599-1614.e2
Andersson-Rolf, A., Mustata, RC., Merenda, A., Kim, J., Perera, S., Grego, T., Andrews, K., Tremble, K., Silva, JC., Fink, J., Skarnes, WC., Koo, BK. (2017). One-step generation of conditional and reversible gene knockouts. Nat Methods. 14(3):287-289
Stange, DE., Koo, BK., Huch, M., Sibbel, G., Basak, O., Lyubimova, A., Kujala, P., Bartfeld, S., Koster, J., Geahlen, JH., Peters, PJ., van Es, JH., van de Wetering, M., Mills, JC., Clevers, H. (2013). Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium. Cell. 155(2):357-68
Koo, BK., Spit, M., Jordens, I., Low, TY., Stange, DE., van de Wetering, M., van Es, JH., Mohammed, S., Heck, AJ., Maurice, MM., Clevers, H. (2012). Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 488(7413):665-9