Reprogramming Aggressive Cancer Cells Into Harmless Ones

UCLA scientists have identified a potential new strategy for treating glioblastoma, the deadliest form of brain cancer, by reprogramming aggressive cancer cells into harmless ones.  

The findings, published in the Proceedings of the National Academy of Sciences, demonstrate that combining radiation therapy with a plant-derived compound called forskolin can force glioblastoma cells into a dormant state, making them incapable of dividing or spreading.

When tested in mice, the addition of forskolin to radiation prolonged survival, offering a potential new avenue for combating glioblastoma, a disease with limited treatment options and a median survival time of just 15 to 18 months after diagnosis.

“Radiation therapy, while effective in killing many cancer cells, also induces a temporary state of cellular flexibility,” said Dr. Frank Pajonk, professor of radiation oncology at the David Geffen School of Medicine at UCLA and the study’s senior author. “We found a way to exploit this flexibility by using forskolin to push these cells into a non-dividing, neuron-like or microglia-like state.”

Glioblastoma is notoriously difficult to treat, largely due to the cancer cell’s ability to divide uncontrollably and the protective blood-brain barrier that limits the effectiveness of therapies. Current standard treatments—surgery followed by chemotherapy and radiation—have remained unchanged for two decades. A key problem is the ability of glioma stem cells to regenerate tumors after treatment and resist conventional therapies, making them a primary reason for treatment failure.

Recent discoveries suggest that radiation not only kills some glioblastoma cells, but also temporarily makes the glioma stem cells more flexible, or adaptable, providing an opportunity to alter their identity. 

Building on this concept, the UCLA researchers decided to look at the combination of radiation and forskolin, a drug compound known to influence cell differentiation by promoting the maturation of cells into neurons, which do not divide uncontrollably like cancer cells.

“Our approach is unique because it leverages the timing and effects of radiation,” said Dr. Ling He, an assistant project scientist in UCLA’s department of radiation oncology and first author of the study. “Unlike traditional therapies that force cancer cells to mature, we use radiation to create a temporary, flexible state, making glioma cells easier to guide into specialized, less harmful types. By adding forskolin at the right moment, we push these cells to become neuron-like or microglia-like, reducing their potential to regrow into tumors.”

To test whether forskolin could reprogram these cells, the team of scientists examined the combined treatment’s effects on cellular behavior, including the expression of neuronal markers, cell cycle distribution and proliferation. Gene expression changes were analyzed using RNA sequencing, while single-cell RNA sequencing revealed how individual glioblastoma cells transitioned into new phenotypes. The impact on glioma stem cells was assessed through limiting dilution assays. The approach was then tested in mouse models to assess its ability to improve survival.

The researchers found that the forskolin was able to cross the blood-brain barrier, significantly depleting glioma stem cells and slowing tumor proliferation.

This approach also significantly slowed tumor growth in mice and, in some cases, led to long-term tumor control. In the highly aggressive and fast-growing model, the combination therapy extended the median survival from 34 days to 48 days. Similarly, in the less aggressive glioma mouse model, the median survival increased to 129 days with the combination treatment, compared to 43.5 days in mice treated with radiation alone. Importantly, the sublethal radiation doses used have minimal effects on their own, noted the researchers.

“These findings highlight the potential of this dual therapy to substantially improve survival in glioblastoma models,” said He.

Researchers were also surprised to find that glioma cells can change into microglia-like cells, a type of immune cell in the brain. Normally, these two cell types come from completely different origins during development. Microglia come from mesoderm, a layer that forms things like blood and immune cells, while glioma cells are thought to come from ectoderm, a layer that forms brain and nerve cells. However, in the unique environment of a tumor, these cancer cells can adapt and "switch identities" between different types of cells.

“Our ultimate goal is to one day transform the standard of care for glioblastoma,” said Pajonk, who is also a member of the UCLA Health Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “By targeting glioma cell plasticity and leveraging the multipotent state induced by radiation, this research offers a promising strategy to disrupt tumor progression and enhance patient survival.”

Although the study shows promising results, the researchers observed that some mice eventually experienced a recurrence, emphasizing the need to refine dosing and explore alternative dosing strategies to improve the long-term durability of tumor response.

Reference: He L, Azizad D, Bhat K, et al. Radiation-induced cellular plasticity primes glioblastoma for forskolin-mediated differentiation. PNAS. 2025;122(9):e2415557122. doi: 10.1073/pnas.2415557122

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