Ca2+-mediated rewiring of cell homing and fusion to VEGF sources

•Engineered mammalian cell line to home towards a cell colony expressing VEGF.•Mechanism for homing is shown to be calcium mediated.•With pH-dependent fusogenic proteins, these homing cells initiate pH-dependent fusion upon reaching the cell colony.

Challenges of cell-based cancer therapy include effectively homing therapeutic cells to the disease site and producing a controlled response in recognition of the microenvironment. While stem cells have been intensively studied for treating cancer as they naturally home towards sites of injury, they have drawbacks due to their pluripotency. In this paper we have shown that a stable HEK293 cell line expressing VEGFR2 and CarQ (an engineered Ca2+-sensitive RhoA) can home towards a cell colony expressing VEGF. Upon VEGF binding to VEGFR2, a Ca2+ signal is produced that in turn activates CarQ-mediated cell blebbing. With the addition of VSVG, these homing cells can further initiate pH-dependent fusion upon reaching the cell colony. This protein system can form the basis of engineering cells for therapeutic intervention by homing and inhibiting tumour growth by pH-dependent fusion.

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