NrasG12D induces CNS tumors in mice.

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NrasG12D induces CNS tumors in mice. NrasG12D induces CNS tumors in mice. A, Kaplan–Meier plot showing survival in months (mo) of study mice. The experimental groups consisted of Nras+/LSL-G12D;Tyr::CreA/° (+/G12D; n = 33) and NrasLSL-G12D/LSL-G12D; Tyr::CreA/° (G12D/G12D; n = 23) mice. The control groups consisted of Tyr::CreA/° (n = 22), Nras+/LSL-G12D (n = 13), and NrasLSL-G12D/LSL-G12D (n = 15)mice. B, photographs showing representative whole-brain and sagittal sections of the brains of control,Nras+/LSL-G12D;Tyr::CreA/° (+/G12D), and NrasLSL-G12D/LSL-G12D;Tyr::CreA/° (G12D/G12D) mice. C, photomicrograph of an H&E-stained brain section from an NrasLSL-G12D/LSL-G12D;Tyr::CreA/° mouse (boxed area in the bottom image of B), displaying proliferation of pigmented melanocytes in the leptomeninges along the external surface of the brain parenchyma (black arrow). Scale bar, 100 μm. D, photomicrograph of an H&E-stained frontal lobe melanoma from an NrasLSL-G12D/LSL-G12D;Tyr::CreA/° mouse, showing leptomeningeal spread of melanoma cells (black arrows). Scale bar, 1 mm. E, photomicrograph showing nuclear Ki67 staining (white arrows) of a representative melanoma from an NrasLSL-G12D/LSL-G12D;Tyr::CreA/° mouse. Note that some cells are melanin laden (black arrowheads). Scale bar, 20 μm. L, D. leptomeninges; P, brain parenchyma. F, high-power photomicrograph of boxed area in D of an H&E-stained melanoma with atypical, epithelioid cells. Tumor cells frequently presented intracytoplasmic melanin (black arrowheads). Scale bar, 25 μm. G, photomicrograph showing HMB45/MelanA staining in a representative melanoma from an NrasLSL-G12D/LSL-G12D;Tyr::CreA/° mouse. Note the predominant membranous staining and presence of intracytoplasmic deposits of melanin in the melanoma cells (black arrowheads). Scale bar, 50 μm. H, Western blot analysis of ppERK and total ERK levels of Nras-mutant melanoma cells following MEK inhibition for 3 hours using PD184352, U0126, and AZD6244. I, in vivo allograft experiment, using Nras-mutant cells from a mouse brain melanoma showing the effect of the MEK inhibitor PD184352 on intradermal tumor growth in C57Bl/6 mice (n = 6 PD184352-treated mice and 9 vehicle-treated mice). Malin Pedersen et al. Cancer Discovery 2013;3:458-469 ©2013 by American Association for Cancer Research