Canonical TGF-Beta Pathway Activity Is a Predictor of SHH-Driven Medulloblastoma Survival
Donya Aref, Connor J Moffatt, Sameer Agnihotri, Adrian Dubuc, Michael D Taylor, Arie Perry, Charles Eberhardt, Sidney Croul. University of Toronto, Toronto, ON, Canada; Hospital for Sick Children, Toronto, ON, Canada; UCSF, San Francisco, CA; Johns Hopkins University, Baltimore, MD
Background: Medulloblastoma, an embryonal neuroepithelial tumour arising in the cerebellum, is the most common malignant brain tumor of childhood. Although current treatment regimens have significantly improved survival over the past decades, recurrent and/or metastatic MB still spell poor prognosis for patients. Aggressiveness is marked by increased growth and decreased responsiveness to available therapies. However the molecular changes that underlie these pathophysiological behaviors during medulloblastoma progression are not well understood.
Design: To further identify pathways of signaling that contribute to medulloblastoma metastasis and recurrence we decided to undertake an unbiased, whole genome expression study. We performed microarray experiments, using human patient matched primary and recurrent or metastatic samples. This was supplemented with microarray data derived from murine samples from two different mouse models of medulloblastoma, the Ptch+/- and Smo/Smo models, that present with differing clinical histories and disease aggressiveness.
Results: At both the human and murine levels we identified the Transforming Growth Factor-beta (TGF-beta) as a potential contributor to medulloblastoma progression/metastasis. Smad3, a major downstream component of the TGF-β pathway, was also evaluated using immunohistochemistry in both developing and malignant human and murine tissue and was shown to correlate with disease progression. Currently we are in the process of assessing the contribution of this signaling pathway in an in vitro setting.
Conclusions: This work identifies TGF-β as a potential contributor to medulloblastoma progression and metastasis both at the level of RNA and protein expression in the human and murine species. To our knowledge, this is the first study that implicates TGF-β as a contributor to medulloblastoma progression and metastasis.
Monday, March 4, 2013 8:00 AM
Proffered Papers: Section G1, Monday Morning