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Injury promotes sarcoma development in a genetically and temporally restricted manner
David Van Mater, … , Sandeep Dave, David G. Kirsch
David Van Mater, … , Sandeep Dave, David G. Kirsch
Published October 18, 2018
Citation Information: JCI Insight. 2018;3(20):e123687. https://doi.org/10.1172/jci.insight.123687.
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Research Article Oncology

Injury promotes sarcoma development in a genetically and temporally restricted manner

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Abstract

Cancer results from the accumulation of genetic mutations in a susceptible cell of origin. We and others have also shown that injury promotes sarcoma development, but how injury cooperates with genetic mutations at the earliest stages of tumor formation is not known. Here, we utilized dual recombinase technology to dissect the complex interplay of the timing of KrasG12D activation, p53 deletion, and muscle injury in sarcomagenesis using a primary mouse model of soft tissue sarcoma. When mutations in oncogenic Kras and p53 are separated by 3 weeks, few sarcomas develop without injury. However, the transformation potential of these tumor-initiating cells can be unmasked by muscle injury. In the absence of Kras mutations, injury of the muscle with global deletion of p53 results in sarcomas with amplification of chromosomal regions encompassing the Met or Yap1 gene. These findings demonstrate a complex interplay between the timing of genetic mutations and perturbations in the tumor microenvironment, which provides insight into the earliest stages of sarcoma development.

Authors

David Van Mater, Eric Xu, Anupama Reddy, Leonor Añó, Mohit Sachdeva, Wesley Huang, Nerissa Williams, Yan Ma, Cassandra Love, Lanie Happ, Sandeep Dave, David G. Kirsch

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Figure 1

Muscle injury restores the transformation potential of cells harboring activated Kras.

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Muscle injury restores the transformation potential of cells harboring a...
(A) Schematic of experiment. Rosa26CreER/CreER; Trp53fl/fl; KrasFSF-G12D/+ (R26CreER; p53fl; KFRT) mice were treated with an intramuscular (IM) injection of adeno-FlpO to activate Kras on day 0, followed by treatment with intraperitoneal (IP) tamoxifen to delete p53 on day 0, 10, or 21. Additional groups of mice were treated with IM adeno-GFP or IM cardiotoxin on day 21 in addition to IP tamoxifen. (B) There is a marked delay in sarcoma formation in R26CreER; p53fl; KFRT mice as the time between Kras activation and p53 deletion is extended from 0 to 21 days. Muscle injury with IM cardiotoxin, but not IM adeno-FlpO, restores the transformation potential of Kras-activated, p53-deleted cells. (C) Bar graph presenting the same data as in B. (D) H&E-stained muscle sections obtained from mice 7 days after the start of the experiment either without treatment or with IM adeno-FlpO or IM cardiotoxin treatment. Evidence of muscle injury and repair (central nuclei noted by arrows) was only observed after cardiotoxin treatment. Scale bar: 50 μm. TMX, tamoxifen.

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