Tumors in Disguise
To evade detection, this brain cancer mimics neurons
By Rachel Tompa, Ph.D.
Illustration by Dan Page
C
ancer cells are really good at playing dress-up. Tumors have developed many ways to evade being killed by drugs or detected by our immune systems by disguising themselves as different kinds of healthy cells. Incurable brain cancer glioblastoma, for example, can mimic human neurons, even growing axons and making active connections with healthy neurons in the brain.
Now, a new study from Sylvester Comprehensive Cancer Center and collaborating institutions has found that this neuron mimicry seems to be essential for the cancer’s treatment resistance. The researchers also identified a class of therapeutics, BRAF inhibitors, that could prevent the tumors’ transition to drug resistance.
These findings were made possible by the researchers’ unique approach to studying glioblastoma. The research team, co-led by Antonio Iavarone, M.D., deputy director of Sylvester and professor of neurological surgery and biochemistry and molecular biology at the Miller School, used a platform they designed to study glioblastoma cells’ full set of proteins, also known as the proteome. The researchers looked for certain modifications on those proteins that indicate enzyme activity in the cell.
“These platforms can provide you a landscape of alterations in individual tumors that you cannot get from genetics alone,” Dr. Iavarone said.
The collaborative research team assembled what is now the largest dataset of its kind — matched tumor samples from 123 glioblastoma patients at the time of diagnosis and when their cancers recurred after initial therapy. By studying the tumors’ proteomes and protein modifications in these samples, the researchers were able to spot important changes not previously seen in similar studies.
This study marks the first time that scientists have used proteomics to study how glioblastomas transition from treatable to treatment resistant. The researchers used their new dataset to identify therapies that could kill these resistant cancers. Looking at kinases — enzymes responsible for phosphorylating other proteins — the researchers used a machine-learning approach they’d previously developed to find the most active kinases in the neuron-like glioblastoma tumors.
One kinase popped to the top of their list: BRAF. The gene encoding for this kinase is commonly mutated in some cancers, including melanoma. But in glioblastoma, BRAF protein levels increase without corresponding changes in the gene. The team wouldn’t have identified its importance in the brain cancer without looking at the cancer proteome.
“Proteomics gives us a much more direct prediction of the proteins’ activity,” Dr. Iavarone said. “We hope that this type of analysis can be seamlessly translated into the clinic as a next-generation precision therapy approach for this very challenging disease and for other resistant cancers, as well.”
Hear more from Dr. Iavarone on the Inside U Miami Medicine podcast. 
