The focus of our proposal is to evaluate whether Dicer inhibition is an effective strategy to selectively target medulloblastoma cells while sparing neurons. While the microRNA-dependent functions of Dicer are well known, recent studies have identified a novel, microRNA-independent function of Dicer in DNA damage repair. As maintenance of genomic integrity is critical for rapidly dividing cells that experience constitutiv replicative stress-induced DNA damage, we evaluated whether Dicer was essential for resolving such DNA damage in vivo in the context of developing cerebellum. In the absence of Dicer, the rapidly dividing cerebellar granule neuron precursors (CGNPs) accumulated DNA damage, which resulted in their degeneration. Remarkably, this degeneration was rescued by p53 deficiency, indicating that Dicer deficiency triggered the activation of the p53-mediated DNA damage pathway. In contrast to the high expression of Dicer in proliferating CGNPs, we found that Dicer is virtually undetectable in cerebellar granule neurons. These results suggest that unlike the proliferating CGNPs, Dicer may not be essential for survival in postmitotic neurons - a hypothesis we will test in a mouse model where we can conditionally delete Dicer selectively in the postmitotic cerebellar neurons. Importantly, we will also evaluate whether inactivation of Dicer could trigger cell death in medulloblastomas. Medulloblastomas are pediatric cerebellar tumors that arise from the aberrant and sustained proliferation of CGNPs beyond the developmental period. Medulloblastoma cells express Dicer, and we predict that, just as seen with the proliferating CGNPs during development, the proliferating medulloblastoma tumor cells also depend on Dicer for resolving endogenous DNA damage. We will test this hypothesis in two mouse models of medulloblastoma where we can readily assess the outcome of Dicer deletion on tumor growth as well as tumor regression. Together, these experiments critically evaluate the unexpected potential of Dicer as a therapeutic target for medulloblastoma with minimal neurotoxicity.
The main goals of our study are to evaluate whether inhibition of Dicer can be an effective strategy for medulloblastoma therapy. The rationale for this approach is based on a novel function of Dicer that appears to be critical for maintaining the survival of rapidly proliferating cells but not neurons. Thus, we anticipate that this approach wil kill brain tumor cells with minimal toxicity to neurons. We will rigorously evaluate the therapeuti potential of targeting Dicer in pre-clinical models of medulloblastoma.
| Swahari, Vijay; Nakamura, Ayumi; Deshmukh, Mohanish (2016) The paradox of dicer in cancer. Mol Cell Oncol 3:e1155006 |
| Swahari, Vijay; Nakamura, Ayumi; Baran-Gale, Jeanette et al. (2016) Essential Function of Dicer in Resolving DNA Damage in the Rapidly Dividing Cells of the Developing and Malignant Cerebellum. Cell Rep 14:216-24 |
