Optically Activated Receptor Tyrosine Kinases (Opto-RTKs) for Investigating Tumor-Stroma Interactions

Optogenetic methods are based on genetically encoded signaling molecules that can be rapidly and non-invasively switched on or off by light. Optogenetic approaches had a big impact in the neurosciences by enabling control of neuronal activity with supreme spatiotemporal resolution. In the last few years the optogenetic toolkit underwent a massive expansion and now enables the optical control of fundamental cell signaling pathways with high precision (1). Different research groups have created approaches for the optical activation of, for instance, the mitogen-activated protein kinase (MAPK), the phospatidylinositol-3 kinase (PI3K) and the Wnt pathway. Deregulation of these signaling pathways in tumor and stromal cells plays a huge role in malignancy. Our group has recently engineered receptor-tyrosine kinases that can be activated by light-induced dimerization (Opto-RTKs)(2). Light thus enabled fine-tuned control of the MAPK, PI3K and phospholipase Cγ (PLCγ) pathways and in consequence regulation of cell behavior relevant for tumors and their microenvironment: cell proliferation, epithelial to mesenchymal transition (EMT) and sprouting of endothelial cells. Current Opto-RTKs from our group include Opto-mFGFR1, Opto-hEGFR and Opto-hRET. The corresponding endogenous receptors are hyperactivated in various tumors and are also relevant in the immune system and for neoangiogenesis. Advantages of optogenetic methods are the ease, specificity, speed and spatial precision with which stimuli can be applied and withdrawn. This unique combination of features can be exploited for a multitude of applications ranging from dissection of intracellular signaling dynamics to cell-type specific and fine-tuned interventions in tumor-stroma co-culture models (3).

(1) Zhang et al., Trends Biotechnol 33:92-100, 2015; (2) Grusch et al., EMBO J 33:1713-26, 2014; (3) Ingles-Prieto et al., Mol Cell Oncol 2: e964045-2, 2014