Customizing Cellular Protein: A New Frontier in Cancer Fight

The traditional view of a cell is a round membrane filled with all the cell’s “machinery”—the nucleus, ribosomes, mitochondria and other organelles that make it work. But that picture is a little misleading, because, in reality, the cell membrane is studded with proteins that stick out beyond the wall of the cell. These proteins perform a wide variety of functions and are crucial in maintaining a signaling pathway between the cell and its outside environment. When one of these proteins is damaged or defective, it can create all sorts of havoc—including telling the cell that it ought to divide and grow uncontrollably. These damaged membrane proteins can also function as masks, hiding a malignant cell from the body’s immune system. Recent advanced cancer therapies have sought to target these damaged membrane proteins with specialized approaches. While only 25% of the more than 20,000 different kinds of proteins in the body are on the cell membrane, approximately half of the drugs we take are directed at them. The next step is to look to cellular function itself as a way to create flexible, versatile platforms that can be customized to more efficiently and effectively fight a wide variety of diseases with fewer side effects. ‘Shredding’ cancer One approach is to identify and destroy the damage-causing proteins—which is exactly what lead authors Ryan Lu and Jithu Krishna, both graduate students in chemistry at UMass Amherst, have done. While previous techniques have focused on biochemical methods of removing such damaged proteins, Lu, Krishna, Thayumanavan, and their co-authors made a surprising discovery. “If you think of the cell surface as a balloon,” says Krishna, “we discovered that when you physically press the balloon, making a dimple, in just the right spot, that deformation triggers the cell’s internalization machinery, routing the damaged surface protein into the cell’s waste disposal mechanism, where it is pulled in and shredded, thereby eliminating the cancerous threat.” The key to physically making this dimple is a “multivalent contact,” performed by a platform the team calls a “polymeric lysosome-targeting chimera,” or PolyTAC. The PolyTAC consists of two pieces: an antibody, which is chosen to recognize the exact finger-print-like biomarker of the specific problem-causing protein, and the polymer, which presses into the cell membrane, making the dimple. In practice, the antibody directs the PolyTAC to the exact spot of the offending protein, the polymer pushes the protein into a dimple that it makes at its base, and then the cell takes over by shredding and disposing of the cancer-causing protein. “There are thousands of different proteins studding the surface of the cell, like a lawn full of weeds” says Lu. “Our PolyTAC zeroes in on the specific weed and routes it to the shredder machinery in the cell to destroy it, thanks to the physical contact made by the polymer.” Custom tailoring cancer cells While the PolyTAC approach, like most protein therapies, focuses on eliminating problem proteins, Shuai Gong, who earned his Ph.D. in chemistry at UMass Amherst, and Jingyi Qiu, a biomedical engineering graduate student in the Riccio College of Engineering, developed a platform that, by delivering fully functional proteins to the cell’s surface, essentially reprogram a cancerous cell so that it returns to its normal, healthy function. “The platform that we built is called an ‘artificial cell-derived vesicle,’ or ACDV,” says Gong, “and it allows us to directly fix what’s wrong with the cell by adding proteins, in real time, using a flexible process.” “This allows for personalized therapies,” adds Qiu, whose previous research in cell fusion set the stage for the ACDV work. “For example, we can reprogram the cell to essentially remove the mask that it wears to avoid detection by the body’s immune system. Or we can reprogram it so that it stops dividing pathologically.” The team successfully demonstrated its technique by implanting four different proteins in the cellular wall. With a little chemistry, they believe that they could do the same with many of the therapeutic proteins currently on the market. The great advantage of this method is that instead of working with damaged proteins, it becomes possible to incorporate perfectly functional ones. “By transforming the display of proteins on the cell’s surface,” sums up Thayumanavan, “we can custom-tailor the way the cell functions.”