Brain tumor: Key found for suppression of growth in medulloblastomas

Medulloblastoma is the most common brain tumor in children, and its treatment remains inefficient. The work of a team of researchers led by Luca Tiberi and Pierre Vanderhaeghen (Université libre de Bruxelles (ULB), WELBIO, IRIBHM and ULB Neuroscience Institute (UNI)) opens new perspectives on the diagnosis and treatment of these brain tumors. They discovered a key factor called BCL6, able to suppress the growth of medulloblastomas in mice and in human tumor cells in culture. This work is in press in the journal Cancer Cell 1.

Researchers first discovered that BCL6, a factor controlling gene expression, controls the conversion of neural stem cells into nerve cells in a part of the brain called cerebellum. The researchers then investigated how BCL6 promotes neurogenesis in the cerebellum. They found that BCL6 acts as an epigenetic "switch" by turning off the gene expression of a major signaling pathway called "Sonic Hedgehog," which normally pushes the neural stem cells to proliferate more and remain undifferentiated. These data provide important information on the mechanisms of brain development, but have also led researchers to examine the role of BCL6 in tumorigenesis of the brain.

Indeed, the signaling pathway "Sonic Hedgehog had previously been involved in the initiation and growth of a tumor called medulloblastoma (the most common form of brain cancer in children). In this contest the Sonic pathway is a therapeutic target, and Sonic antagonist drugs have already been developed against these tumors, but the tumors quickly develop resistance to these treatments. This led the researchers to test whether and how BCL6 could suppress gene expression in response to 'Sonic' signals also in tumors cells such as medulloblastoma.

Firstly, they tested the effect of BCL6 on cells cultured from medulloblastomas: This revealed a drastic suppression of the growth of these human tumor cells, through the inhibition of the "Sonic Hedgehog" signals.

Next, the researchers tested the effects of BCL6 in a model of medulloblastoma in mice. Remarkably, this revealed that the BCL6 overexpression in the cells at the origin of these tumors was sufficient to block their tumor growth, and thus largely prolong the survival of mice (Figure).

Furthermore, the researchers studied mice in which the BCL6 gene is disabled, and it this case medulloblastomas appeared after a few months, indicating that BCL6 is a 'tumor suppressor' gene.

Finally, the researchers studied the finer molecular mechanisms of action of BCL6 and identified another factor acting with BCL6, called BCOR, which was previously found to be mutated in many cases of human medulloblastomas.

These basic research findings, focusing initially on the normal development of the brain, have important implications for the understanding, diagnosis and treatment of cancers. On the one hand it identifies BCL6/BCOR as an attractive target to activate in order to suppress the growth of medulloblastoma.

Furthermore, this work shows that BCL6 is a natural suppressor of medulloblastomas, whereas earlier work showed that BCL6 is also a pro-cancer factor in many forms of blood cancer (leukemia, lymphoma). Thus, the same factor can act as an an oncogene in the blood, and an anti-oncogene in the brain, illustrating the complexity of the genetics of cancer, which may have other clinical implications. Indeed, drugs have recently been developed to inhibit BCL6 to slow the growth of some blood cell tumors. In light of the data of Tiberi et al., the use of BCL6 inhibitors against blood cell tumors could result in the initiation of medulloblastoma or other brain tumors.