Intravital imaging of plasticity during tumor growth and metastasis

Abstract

Most tumors consist of a heterogeneous mixture of genetically and epigenetically distinct tumor cells. In addition, tumors display regional differences in the tumor microenvironment comprising non-transformed cell types such as immune cells and non-cellular factors including growth factors and the extracellular matrix. As a consequence of this intra-tumor heterogeneity, individual tumor cells may differ in a variety of features such as metastatic behavior and sensitivity to cytotoxic drugs. Complications after metastatic spread and relapse after therapy are the major cause of cancer-related deaths, but the precise contribution of intra-tumor heterogeneity to these clinical problems is still not fully understood.

To investigate the complexity of heterogeneous tumors, until recently, most studies relied on the use of relatively large numbers of cells, for example for genome-wide sequencing or proteomics. However, the presence of rare but biologically relevant cells is difficult to resolve from these data, and thus these methods may not completely reveal the full spectrum of heterogeneity. While techniques such as histochemistry or single cell sequencing significantly contributed to a more detailed understanding of intra-tumor heterogeneity on a single cell level, these methods only provide a static view and do not assess the adaptive properties and functional role of individual cells present in living organisms. To study in vivo dynamics of single cells within heterogeneous tumors, in the studies described in this thesis we make use of fluorescent mouse models and intravital microscopy, a technique by which individual cells inside a living organism can be visualized.