Research News

Even after decades of research, glioblastoma remains one of the most aggressive and difficult to treat brain cancers. In a new JCI Insight study led by Peiwen Chen, PhD, Cleveland Clinic researchers describe how cancerous and healthy cells in the tumor microenvironment communicate to drive tumor progression.  

Cancer stem cells driving tumor growth in the glioblastoma-affected brain trick a subset of immune cells called tumor associated-macrophages into providing the tumor with the molecules it needs to survive. The research team also found blocking this molecular conversation with therapies could be the key to effectively targeting this deadly cancer. 

What is the tumor microenvironment? 

The tumor microenvironment describes all of the cancerous and healthy tissue, veins, cells and molecules inside of and surrounding a tumor. Unlike healthy areas of our body further away from the cancer cells, the tumor can influence or co-opt noncancerous areas in the tumor microenvironment. The tumor microenvironment’s reach depends on how far out the tumor cells can send signals to surrounding noncancerous cells. 

Capturing the conversation with cancer stem cells 

Think of all the cells in the tumor microenvironment (cancerous or otherwise) as having a “conversation” that triggers specific activities.  

“Cancers like glioblastoma are exceedingly hard to treat because the different cells in the tumor microenvironment constantly communicate to help the tumor resist therapy,” Dr. Chen says. “They do this by sending out molecules that trigger specific responses in nearby cells, especially immune cells. If we want to improve the survival and cure rates of glioblastoma, understanding and blocking these molecular signals is crucial.” 

The Chen Lab found that tumor-associated macrophages make and deliver a molecule called GPNMB to tumors in glioblastoma. Doing so feeds cancer stem cells, a small population of cells that can regenerate continuously and that can develop into other types of cancer cells the tumor needs to survive. The molecule helps cancer stem cells maintain key regenerative and metabolic abilities like self-renewal and glycolysis. Even if a treatment destroys 99% of cancer cells in a patient’s body, the tumor can still regenerate if enough stem cells survive. 

“There is a constant, dynamic conversation happening between glioblastoma stem cells and tumor-associated macrophages. In this case, the tumor doesn’t appear to produce GPNMB on its own, so to sustain its stem cell population, it needs to ask noncancerous cells to supply it,” says study first author Yang Liu, PhD, a postdoctoral fellow in the Chen Lab. “Glioblastoma stem cells seem to reprogram tumor-associated macrophages to produce GPNMB, though the exact molecular mechanism behind this reprogramming still needs further investigation.” 

This new insight provides more options for glioblastoma therapeutics development. Although blocking other signals from tumor-associated immune cells increased survival rates from 0 to 60% in other preclinical studies from the Chen Lab, diverse treatment options are essential as no one glioblastoma case is the same, Dr. Chen says. 

“Discovering new signaling axes in the glioblastoma tumor microenvironment gives us a broader and more precise toolkit,” Dr. Liu explains. “It allows us to design combination therapies that can be personalized to each tumor’s unique microenvironment to overcome treatment resistance.”