In glioblastoma multiforme (GBM), the most common and lethal brain tumor, lack of differentiation makes a big, and bad, difference.
GBM tumors are full of cells that refuse to grow up, immature cells produced by cancer stem cells that fail at terminal differentiation -- the final step to becoming a mature, useful cell. These flawed precursor cells are a major source of cellular diversity, or heterogeneity, a hallmark of cancer that makes it hard to treat.
"If glioblastoma cells were to undergo differentiation, the tumor would stop growing," says Jian Hu, Ph.D., instructor in Genomic Medicine.
GBM cells are full of genetic events that promote stem cell-like activity. But Hu and colleagues wondered what might be missing from these tumors that would otherwise prevent such activity.
In research published this week in the online Early Edition of the Proceedings of the National Academy of Sciences, the researchers report gene circuitry that forces precursor cells to mature is deleted or impaired in glioblastoma.
"We've also shown that when this terminal differentiation circuitry is gone, precursor cells get stuck in the middle and produce many different cell types, causing tumor growth," Hu said.
The PNAS paper is the Inaugural Paper for senior author and MD Anderson President Ronald DePinho, M.D. Inaugural Papers are published in PNAS by newly elected members of the National Academy of Sciences. DePinho, who was elected in 2012, discusses this research in a PNAS interview also online.
Gene-splicer forces cells to try to mature, then die
Normal neural stem cells divide into a copy of themselves and a copy of a precursor cell destined to differentiate into a specific type -- neurons, astrocytes or oligodendrocytes. GBM stem cells reproduce themselves and the immature cells.
Hu and colleagues surveyed The Cancer Genome Atlas GBM database for genes involved in nervous system development that are also frequently deleted in GBM. Of 71 identified, the gene-splicing factor A2BP1 reduced GBM cell colony formation.
By profiling 430 TCGA glioblastoma samples, they found A2BP1 deleted in 10% of tumors and its protein absent in 90%. It's deleted in other solid tumor types, including colon cancer.
Silencing A2BP1 in a GBM-prone mouse model led to tumor formation at 15 weeks, while control mice were tumor-free at 25 weeks. A2BP1 worked by forcing immature cells to attempt differentiation, which led to their destruction by apoptosis, or programmed cell death.
Myt1L activates A2BP1, which splices TPM1 to block cancer
They searched for proteins that usually activate A2BP1 that might also be impaired. The team found that Myt1L activates A2BP1 and is itself deleted (5%) or absent (80%) in GBM tumors.
Expressing or suppressing Myt1L in human and mouse GBM cell lines had the same effects as doing either with A2BP1. The cause of Myt1L's impairment in glioblastoma is unknown for now.
Finally, they found that A2BP1 splices a known tumor suppressor called TPM1 in a way that raises levels of the form of the TPM1 protein with the greatest cancer-fighting capacity.
Their research suggests differentiation therapies that work in some blood malignancies are likely to be less effective against GBM. Their findings could lead to biomarkers that indicate who should get this therapy and suggest a combination of drugs to inhibit stemness and activate Myt1L-A2BP1 differentiation might provide an effective treatment.
PNAS DePinho interview
MD Anderson news release