Bmi1 and Hedgehog Signaling in Medulloblastoma Pathogenesis.

Abstract

Medulloblastoma is the most common malignant brain tumor in children, and occurs in up to 5% of patients with Gorlin syndrome, a familial cancer susceptibility disorder characterized by inappropriate activation of the Hedgehog (Hh) signaling pathway. Activation of Hh signaling is also seen in a significant fraction of sporadic medulloblastomas, many of which are believed to arise from the external granular layer (EGL) of the cerebellum, a transient, highly proliferative pool of Hh-responsive neural progenitors that disappears within the first several weeks of life, in mice. I investigated where and when medulloblastomas arise using a novel mouse model expressing SmoA1, a constitutively activated allele of the proximal Hh effector Smo, in the brain in a temporally restricted manner. SmoA1 induction in the developing cerebellum induced 100% penetrant medulloblastoma as early as two weeks old. Once the EGL had disappeared, however, mice were completely refractory to induction of de novo medulloblastomas, providing strong evidence that the EGL represents a bona fide pool of cells with the potential to become medulloblastoma, and that other SmoA1-expressing cells in adult mice are not competent to form medulloblastomas. To test whether SmoA1-induced medulloblastomas remain dependent on continued Hh signaling, I repressed transgene expression in established tumors. I observed that even relatively brief 3-week inhibition of SmoA1 resulted in complete and durable elimination of tumors. Tumors did not recur following resumption of transgene expression, suggesting that no dormant tumor cells remain. This is a timely finding, as a Hh antagonist is currently in Phase II clinical trials for antitumor therapy. Lastly, I examined the dependence of tumor formation on the stem cell maintenance gene Bmi1, which is required for physiologic cerebellar development and is expressed in Hh-active human medulloblastomas. Breeding SmoA1 mice onto a Bmi1-null background revealed that in the absence of Bmi1, tumor initiation occurs, but lesions do not progress to frank medulloblastomas. This implicates Bmi1 as a key downstream target of Hh in a pathologic setting. The work presented herein provides several important insights into the pathogenesis of Hh-driven medulloblastoma, and may suggest a more general role for Bmi1 in Hh-mediated cancer.