Unbiased niche identification and manipulation in stem cells and cancer

ongoing

For the longest time, researchers assumed that stemness is a cell-intrinsic feature. However, recently my work and the work of others have shown that specific microenvironments can restore stem cell identity in differentiated epithelial cells or induce transitions from one mature cell type to another. This instructive capacity of niches is equally important in homeostasis and disease. Like stem cells, cancer cells only survive in particular environments that nurture and protect them. This is particularly evident in the process of metastasis where only 1 out of 10 000 circulating tumor cells will find a suitable niche to grow. Nevertheless, our understanding of stem cell and cancer niches is still very limited. The main reason for this knowledge gap is the lack of suitable analysis tools. In the course of the EnviroTag project my team and I will generate a novel type of in vivo reporter system, which can label and genetically engineer the cellular environment of any cell of interest. We will use a multidisciplinary approach that combines the EnviroTag system with single cell sequencing, 3D-reconstructed confocal microscopy and organoid technology to study the dynamic roles of niche composition during tissue regeneration and cancer progression. Focusing on the gastro-intestinal tract, we will investigate how changes in the stem or cancer cell microenvironment control success and failure during tissue repair and the earliest steps of metastasis. Thereby, we will generate a new understanding of microenvironmental dynamics and uncover new regulatory mechanisms, signals and cell types that can be targeted to stimulate tissue regeneration or prevent metastatic spread. Objectives: 1) Establish a spatial in vivo reporter system for microenvironmental labelling and manipulation 2) Map functional interactions of stem cells and their niches during homeostasis and active regeneration 3) Identify the minimal niche requirements for metastatic engraftment and proliferation