Abstract
Cell-cell interactions influence all aspects of development, homeostasis, and disease. In cancer, interactions between cancer cells and stromal cells play a major role in nearly every step of carcinogenesis. Thus, the ability to record cell-cell interactions would facilitate mechanistic delineation of the role of the cancer microenvironment. Here, we describe GFP-based Touching Nexus (G-baToN) which relies upon nanobody-directed fluorescent protein transfer to enable sensitive and specific labeling of cells after cell-cell interactions. G-baToN is a generalizable system that enables physical contact-based labeling between various human and mouse cell types, including endothelial cell-pericyte, neuron-astrocyte, and diverse cancer-stromal cell pairs. A suite of orthogonal baToN tools enables reciprocal cell-cell labeling, interaction-dependent cargo transfer, and the identification of higher order cell-cell interactions across a wide range of cell types. The ability to track physically interacting cells with these simple and sensitive systems will greatly accelerate our understanding of the outputs of cell-cell interactions in cancer as well as across many biological processes.
Highlights
Cell-cell interactions contribute to almost all physiological and pathological states (Deb, 2014; Komohara and Takeya, 2017; Konry et al, 2016; Zhang and Liu, 2019)
To create a system in which a fluorescent signal could be transferred between neighboring cells, we adapted a synthetic ligand-receptor system based on the expression of surface GFP on sender cells and a cell surface anti-GFP nanobody on receiver cells (Fridy et al, 2014; Lim et al, 2013; Morsut et al, 2016)
Our data document the ability of diverse primary cell types to serve as both sender and receiver cells, suggesting that the GFP-based Touching Nexus (G-baToN) system is simple, sensitive and rapid, and generalizable
Summary
Cell-cell interactions contribute to almost all physiological and pathological states (Deb, 2014; Komohara and Takeya, 2017; Konry et al, 2016; Zhang and Liu, 2019). While secreted factors relaying pro- or anti-tumorigenic signals have been extensively investigated, the impact of direct physical interactions between cancer cells and stromal cells remains understudied (Bendas and Borsig, 2012; Dittmer and Leyh, 2014; Nagarsheth et al, 2017). A greater understanding of the constellation of direct interactions that cancer cells undergo will deepen our understanding of tumor ecology and has the potential to uncover novel therapeutic opportunities
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