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A spatially and temporally restricted mouse model of soft tissue sarcoma

Abstract

Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.

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Figure 1: A mouse model for high-grade soft tissue sarcoma with myofibroblastic features.
Figure 2: Molecular imaging of primary sarcomas before and after surgical resection.
Figure 3: Sensitivity and specificity of the HHD.
Figure 4: Soft tissue sarcomas in the mouse metastasize to the lungs.
Figure 5: Dissecting the p53 pathway in soft tissue sarcomas and sinonasal adenocarcinomas.

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Acknowledgements

We thank A. Berns (Netherlands Cancer Institute) for providing the Trp53Fl mice and R. Depinho (Dana Farber Cancer Institute) for the Cdkn2afFl mice. We thank W. Strob and S. Schmidt from Siemens AG - Medical Solutions, Erlangen, for providing the prototype handheld near-infrared imaging device. We also thank S. Rhee and P. Waterman for performing the MRI and FMT imaging, K. Reilly for suggestions on immunohistochemistry, K. Mercer for performing necropsies, and members of the Jacks lab for advice and critical reading of the manuscript. This work was supported by the Howard Hughes Medical Institute (T.J.), partially by Cancer Center Support (core) grant P30-CA14051 from the US National Cancer Institute (to T.J.), R24 CA92782 (to R.W.), P50 CA86355 (to R.W.), U54 CA119349 (to R.W. and T.J.), KO8 CA 114176 (to D.G.K.), the Leaf fund (to D.G.K.), and the Burroughs Wellcome Fund (to D.M.D.). T.J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar.

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Correspondence to Tyler Jacks.

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Competing interests

Ralph Weissleder is a founder of and holds shares of stock in VisEn Medical, a company that is developing experimental imaging technologies.

Christian Schultz is employed by Siemens Medical Solutions USA, a company that is developing medical imaging equipment and technologies.

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Supplementary Figures 1–4, Supplementary Tables 1–2, Supplementary Methods, Supplementary Note (PDF 627 kb)

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Kirsch, D., Dinulescu, D., Miller, J. et al. A spatially and temporally restricted mouse model of soft tissue sarcoma. Nat Med 13, 992–997 (2007). https://doi.org/10.1038/nm1602

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