The Smo/Smo Model: Hedgehog-Induced Medulloblastoma with 90% Incidence and Leptomeningeal Spread

Abstract

Toward the goal of generating a mouse medulloblastoma model with increased tumor incidence, we developed a homozygous version of our ND2:SmoA1 model. Medulloblastomas form in 94% of homozygous Smo/Smo mice by 2 months of age. Tumor formation is, thus, predictable by age, before the symptomatic appearance of larger lesions. This high incidence and early onset of tumors is ideal for preclinical studies because mice can be enrolled before symptom onset and with a greater latency period before late-stage disease. Smo/Smo tumors also display leptomeningeal dissemination of neoplastic cells to the brain and spine, which occurs in many human cases. Despite an extended proliferation of granule neuron precursors (GNP) in the postnatal external granular layer (EGL), the internal granular layer formed normally in Smo/Smo mice and tumor formation occurred only in localized foci on the superficial surface of the molecular layer. Thus, tumor formation is not simply the result of over proliferation of GNPs within the EGL. Moreover, Smo/Smo medulloblastomas were transplantable and serially passaged in vivo, demonstrating the aggressiveness of tumor cells and their transformation beyond a hyperplastic state. The Smo/Smo model is the first mouse medulloblastoma model to show leptomeningeal spread. The adherence to human pathology, high incidence, and early onset of tumors thus make Smo/Smo mice an efficient model for preclinical studies.

Patched1 deletion increases N-Myc protein stability as a mechanism of medulloblastoma initiation and progression

“…An expanded EGL was observed in this model, similarly in ND2:SmoA1 P14 mice with a constitutively activated Smo gene (Hatton et al, 2008). It may be that other groups have not previously noted an expanded EGL in Ptch1 þ /À mice with analysis carried out by a total of percentage positive 5-bromo-2-deoxyuridine cells of the EGL.…”

Role of MYC in Medulloblastoma

“…Robinson Northcott et al 2012a;Pugh et al 2012;Robinson et al 2012). Numerous mouse models of this disease have been developed by engineering mutations that activate the SHH pathway (Goodrich et al 1997;Hallahan et al 2004;Uziel et al 2005;Zindy et al 2007;Hatton et al 2008;Ayrault et al 2010).…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…The role of Hh signaling in medulloblastomas is also clearly shown in animal models. For example, specific expression of active SMO, SmoM2, in mouse cerebellar granule neuron precursors (ND2:SmoA1 mice) results in formation of medulloblastomas (Hatton et al, 2008).…”