Breast cancer–osteoclast interactions generate hybrid-like cells via non-canonical fusion and cell-in-cell processes

When cancer spreads from its original site to the bones, it faces a hostile and crowded environment. The bone is not just a static scaffold; it is a living tissue constantly being broken down and rebuilt by specialized cells called osteoclasts. These cells act like microscopic demolition crews, dissolving old bone to make room for new growth. In many cases, breast cancer cells that travel to the bone learn to mimic the behavior of these bone cells, a trick that helps them survive and hide from the immune system. Scientists have long known that cancer cells and bone cells talk to each other, usually by sending chemical signals across the space between them. This conversation often leads to a vicious cycle where the cancer triggers the bone cells to break down more bone, releasing nutrients that feed the tumor. However, the precise nature of how these two very different cell types interact on a physical level has remained a mystery.

A team of researchers at City University of Hong Kong and The Chinese University of Hong Kong has now uncovered a startling new way these cells interact. They discovered that breast cancer cells do not just send messages to osteoclasts; they can physically merge with them. Using advanced imaging and genetic tools, the scientists observed that as osteoclasts form and mature, they can engulf nearby cancer cells or fuse directly with them. This process creates a hybrid cell, a single entity that contains the machinery of both a bone-dissolving cell and a cancer cell. These hybrid cells are not just a biological curiosity; they appear to possess a unique set of instructions that allow them to remodel their surroundings, encourage blood vessel growth, and potentially evade the body's defenses. The study suggests that this direct physical merging is a previously overlooked strategy that tumors use to adapt and thrive within the bone.

To understand how this happens, the researchers first looked at human data from patients with breast cancer that had spread to the bone. By analyzing the genetic profiles of thousands of individual cells, they found a small but significant group of cancer cells that were expressing genes typically found only in osteoclasts. These cancer cells were essentially wearing a disguise, carrying the genetic signature of the very cells they were trying to coexist with. This observation hinted that something more than simple chemical signaling was occurring. To test this, the team moved to the laboratory, growing mouse breast cancer cells alongside developing osteoclasts. They labeled the cancer cells with a red fluorescent marker and the osteoclasts with a green one, allowing them to watch the interaction in real time under a microscope.

What they saw was a dynamic and active process. As the osteoclasts began to fuse together to form their large, multi-nucleated structures, they also pulled in the nearby cancer cells. In some cases, a cancer cell would enter an osteoclast while it was still forming, becoming trapped inside the growing cell. In other instances, a fully formed hybrid cell would fuse with another, creating an even larger structure. The researchers captured these events on video, showing cancer cells being incorporated into the cytoplasm of the osteoclasts. Crucially, the cancer cells did not simply die inside; their nuclei remained intact and active, continuing to function while surrounded by the osteoclast material. This confirmed that the two cell types were physically combining to form a new, hybrid state.

The team then isolated these hybrid cells from the culture dishes using a laser to cut them out individually. They sequenced the RNA, the genetic blueprint, of these hybrids to see how their behavior had changed. The results were distinct. The hybrid cells were not just a mix of the two parents; they had developed a unique identity. They showed high activity in pathways related to remodeling the extracellular matrix, which is the structural scaffold that holds cells together, and in pathways that promote the growth of new blood vessels. They also activated specific cancer-related signaling routes, including the PI3K-AKT and Hippo pathways, which are known to drive cell growth and survival. In contrast, the osteoclasts that had not merged with cancer cells showed a different profile, focused more on standard immune responses and inflammation.

The researchers also investigated what happened to the cancer cells themselves when they were near osteoclasts. They found that the presence of osteoclasts, particularly when the cells were touching, caused the cancer cells to change their own genetic expression. The cancer cells began to turn on genes associated with blood cell development and osteoclast function, effectively adopting some of the traits of the bone cells. This change was much stronger when the cells were in direct contact compared to when they were separated by a barrier that allowed only chemical signals to pass. This suggests that physical touch is a critical trigger for this transformation. To confirm this in a living system, the team injected labeled cancer cells into mice that had been genetically engineered so that only their osteoclasts could activate a specific marker. They found that the cancer cells in the bone, but not in other organs like the liver or lungs, had picked up this marker, proving that the interaction with osteoclasts was happening specifically within the bone environment.

Finally, the researchers looked at the activity of a key protein called YAP1, which is involved in controlling cell growth and shape. They found that in the hybrid cells, the cancer nuclei showed high levels of active YAP1, while the osteoclast nuclei showed low levels. This imbalance suggested that the hybrid cells were in a state that favored rapid growth and division. The presence of these hybrid cells in human patient samples, identified through the same genetic signatures found in the mouse experiments, confirmed that this phenomenon is not just a laboratory artifact but a real feature of human disease. The study concludes that breast cancer cells can physically merge with osteoclasts to create hybrid cells that are uniquely adapted to the bone environment. These hybrids possess a blend of traits that allow them to remodel the bone matrix, recruit blood vessels, and potentially hide from the immune system, offering a new perspective on how tumors establish a foothold in the skeleton.