In what could transform the study of cells’ interactions with their environment, researchers have invented a microscope that can look at live cancer cells in 3D, with high resolution in every direction. Previously, high-resolution live imaging has been done with cells cultured on glass slides, which flattens samples. Live cells are highly sensitive to their surroundings, so the new microscopy strategy—which replaces glass slides with blocks of collagen—could help reveal more natural behaviors. The technique, called microenvironmental selective plane illumination microscopy (meSPIM), uses exceptionally long, thin beams of laser light to trigger fluorescence in a sample, causing it to glow. It can reveal details as small as 300 nanometers while maintaining a wide field of view in samples that mimic real tissues. This could allow researchers to watch complex processes such as cell signaling in cancerous and noncancerous tissue, according to a study published today in Developmental Cell. In that work, the researchers found that melanoma cells behave differently inside the collagen, versus under glass slides, forming a greater number of rounded bulges known as “blebs.” They were able to measure factors such as the size and shape of the blebs and the distribution of particular proteins using algorithms that quantified what the microscope saw. In the lung cancer cell shown above at left, red shades indicate the presence of actin, a structural protein important in cell movement. In the melanoma cell to its right, red indicates activity of a signaling molecule called PI3-kinase. Such images could help researchers learn how cancer cells invade other tissues.