Researchers at Fox Chase Cancer Center have identified a new way that cancer cells avoid the effects of anti-cancer drugs. In a study published in Blood Neoplasia, the team describes how cancer cells can enter and survive within bone marrow fibroblasts, calling this process “cell-in-cell.”
The five-year research project was led by Wang, a professor and physician-scientist at Fox Chase. The findings may change treatment approaches for chronic lymphocytic leukemia (CLL), which is the most common blood cancer in western countries.
“Our discovery that tumor cells can actually get inside bone marrow fibroblast cells, which support the tumor cells in their microenvironment, has never been reported before as a live phenomenon,” said Wang.
“This finding helps to explain why, even when CLL patients initially respond to treatment, many of them carry residual disease and later relapse. We are hopeful that our discovery will lead to treatments that better eliminate residual disease and move toward a cure for cancer,” Wang added.
BTK inhibitors are commonly used to treat CLL. Most patients see an initial improvement with these drugs; however, only about 8% to 11% achieve complete remission without evidence of disease. This leaves many patients with residual disease and at risk for relapse. Wang’s team aimed to understand how some cancer cells persist despite early drug response.
Using confocal microscopy and other methods, researchers examined bone marrow samples from patients. They observed CLL cells entering bone marrow fibroblasts after exposure to BTK inhibitors. The cancer cells inside these fibroblasts survived longer than those outside.
“It’s like the tumor cells are retreating off the street into a house where they’re safer from the street bullies, i.e., the drugs,” said Wang.
The study found that CLL cells increase levels of CXCR4—a receptor protein—when exposed to BTK inhibitors. This leads them toward fibroblasts that produce ligands for CXCR4, allowing entry into these “safe houses.” When researchers blocked CXCR4 using approved drugs for other conditions, they prevented CLL cells from hiding inside fibroblasts.
“If we can block CXCR4, it’s like locking the door of the house where tumor cells wanted to retreat and hide,” said Wang. “This could potentially increase complete response rates through combination therapy using both BTK inhibitors and CXCR4 blockers.”
The cell-in-cell behavior was also seen in follicular lymphoma samples. Researchers believe this mechanism might apply across various cancers.
“We want the larger scientific community to know about this mechanism so other researchers can build on these findings. If we can understand what makes cancer cells persist as residual disease, we can better treat cancer and move toward the ultimate goal of cancer elimination.”
Fox Chase Cancer Center is located in Philadelphia and was founded in 1904. Its president is Dr. Robert Uzzo. The hospital serves as a training facility; according to its 2022 annual report, it performed over 5,000 surgeries and admitted more than 3,400 patients during that year (https://www.foxchase.org/about-us/annual-report).
