Stem Cells in Tissue Regeneration and Cancer
Stem cells are self-renewing cells and are constitutively or conditionally activated during tissue homeostasis and regeneration, respectively. Understanding the biology of stem cells will provide valuable insights into therapeutic applications in regenerative medicine. To date, stem cell studies are profoundly dependent of consensus stem cell markers, which may not fully represent the physiology of stem cells. Moreover, due to the fine interaction between intrinsic and extrinsic factors in modulating stem cells, utilizing animal models is imperative to understand stem cell behavior.
To overcome such technical limitation, we established genetically engineered mouse models using a functional stem cell marker. These mouse models enabled us to visualize, quantify, and perform the cellular and genetic manipulation of stem cells in vivo.
Employing these mouse models, we are solving the following problems:
- What triggers quiescence exit of stem cells upon tissue injury?
- How do we rebuild tissues from isolated tissue stem cells for disease modeling and treatment?
- How do tumor-initiating cells become therapeutically resistant?
- How do we target stemness and cellular plasticity of cancer cells?
- Jun et al., Nature Communications, 2016
- Wang et al., Nature Communications, 2016
Our laboratory is interested in modeling of human cancer using genetically engineered mouse models. Employing the comprehensive approaches including in silico analyses, biochemistry, molecular biology and cell biology, we are identifying several candidate genes as the molecular targets for cancer treatment. Beyond cell line experiments, we have established various mouse models mimicking the pathologic condition of tumor initiation, proliferation, metastasis and suppression.
Genetically Engineered Mouse Models (GEMMs)
To date, we have generated various GEMMs including knock-in, knock-out (germline and conditional), transgenic (doxycycline-inducible). To establish GEMMs, we have employed the following technologies; conventional targeting (targeting vector construction, mouse embryonic stem cell targeting and injection), pronuclear injection, and CRISPR gene editing.
- Wang et al., Nat. Comms. 2016
- Jung et al., Mol Cell 2013
- Jun et al., Cell Reports 2013
- Park et al., Nature 2009
Wnt Signaling in Development and Cancer
Wnt signaling is essential for development, tissue homeostasis and regeneration. However, hyperactivation of Wnt signaling leads to human disease including cancer. Thus, blockade of Wnt signaling will be the potential therapeutic approaches for cancer treatment. However, due to the crucial roles of Wnt signaling in tissue stem cell maintenance and activation, targeting Wnt signaling is still challenging.
To tackle this problem, we are addressing the following questions:
- How do we manipulate Wnt signaling for disease treatment?
- How can cancer-specific Wnt signaling regulators be therapeutically targeted?
Identifying and Targeting Cancer-Specific Wnt Signaling Regulators
Many human cancers harbor genetic or epigenetic deregulation of the key components of Wnt signaling. This setting hyperactivates Wnt/beta-catenin target gene expression (c-Myc, Cyclin D1, etc.), which results in the tumor initiation, proliferation, and metastasis. Intriguingly, despite the homogenous mutations of tumor cells, the activity of Wnt/beta-catenin signaling in tumors is heterogeneous, which is called 'beta-catenin paradox'. Moreover, many recent reports including ours strongly suggest that even Wnt/beta-catenin signaling mutated cells can be negatively controlled by the specific manipulation of Wnt/beta-catenin signaling.
Based on the beta-catenin paradox concept, we have sought to identify cancer-specific Wnt signaling regulators. Our comprehensive approaches identified the cancer-specific Wnt signaling regulators (Mol Cell 2013, Cell Reports, Nat Comms 2016a, Nat Comms 2016b). Furthermore, we found that genetic ablation (knock-out) of these genes significantly inhibits tumor initiation and proliferation in mouse models.
Currently, we are developing the ways to manipulate such Wnt signaling regulators as the new regime of cancer treatment.
- Suh et al., Scientific Reports, 2016
- Jung et al., Oncotarget, 2016
- Wang et al., Nature Communications, 2016
- Wang et al., Dev Cell, 2015
- Jung et al., Mol Cell, 2013
- Jun et al., Cell Reports, 2013
- Park et al., Nature, 2009
- Park et al., Dev Cell, 2006
- Park et al., Dev Cell, 2005
- Kim et al., Nat. Cell. Biol., 2004