Peripheral Axons Form Endoplasmic Reticulum-Rich Conduits With Breast Cancer Cells

Peripheral nerves are active components of the tumor microenvironment, but the physical routes by which sensory axons communicate with cancer cells remain incompletely defined. Here, we show that primary dorsal root ganglion neurons form thin membrane conduits with EMT6 breast cancer cells that contain endoplasmic reticulum (ER). ER-Tracker labeling and neuron-restricted expression of the ER proteins CNPY2 and ATL3 identified ER-rich axonal extensions terminating on cancer cells. Serial-section scanning transmission electron microscopy resolved ER-like membranes within these conduits and at axon-cancer cell interfaces. Scanning electron microscopy and live holotomographic imaging further revealed dynamic contact formation and associated remodeling of the cancer cell surface. These observations define an ER-containing structural interface between sensory axons and cancer cells and provide a framework for testing whether neuronal ER contributes to direct intercellular signaling or material transfer.