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Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor

Abstract

Mutations in the gene encoding the retinoblastoma tumor suppressor predispose humans and mice to tumor development1,2. Here we have assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1+/− animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1+/− mice progress to metastatic medullary carcinomas after loss of Nras. In Rb1+/−Nras+/− animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele. Loss of Nras in Rb1-deficient C cells results in elevated Ras homolog family A (RhoA) activity, and this is causally linked to the invasiveness and metastatic behavior of these cells. These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression.

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Figure 1: Effects of Nras loss on pituitary tumor formation in Rb1+/− mice.
Figure 2: Contribution of Nras loss to C-cell thyroid tumor progression and metastasis in Rb1+/− mice.
Figure 3: Contribution of Nras nullizygosity to the metastatic behavior of Rb1-deficient C cells.
Figure 4: Loss of Nras affects RhoA activity, causing migratory and metastatic behavior of Rb1-deficient C cells.

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Acknowledgements

We thank T. Jacks, R. Kucherlapati and A. Silva for providing mice; F. Giancotti, H. Kitayama, C. Marshall, S. Narumiya, X.-D. Ren, E. Sahai, M. Schwartz and M. Symons for useful reagents; A. Tischler, P. Fotiadou, D.M. Livingston, A. Shamma, T. Miki and C. Das for critical reading of the manuscript; K.-Y. Lee, J. Suh, C. McMahon, J. Lamb, W. Sellers, R. Takahashi and H. Rajabi for advice and encouragement. This work was supported by funding from the National Cancer Institute–Japanese Foundation for Cancer Research Scientist Exchange Program, Massachusetts Prostate Cancer Research Program, Japanese Ministry of Education, Culture, Sports, Science and Technology, The 21st Century Center of Excellence Program, Yamanouchi Foundation for Research on Metabolic Disorders and Public Trust Haraguchi Memorial Cancer Research Fund (C.T.) and the National Cancer Institute (M.L. and M.E.E.).

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Correspondence to Chiaki Takahashi or Mark E Ewen.

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Supplementary Fig. 1

Effects of Nras loss on the survival and phenotypes of Rb1+/− mice. (PDF 134 kb)

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Takahashi, C., Contreras, B., Iwanaga, T. et al. Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor. Nat Genet 38, 118–123 (2006). https://doi.org/10.1038/ng1703

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