Department of Pediatrics, Division of Hematology-Oncology.
Department of Radiation Oncology.
JCI Insight. 2018 Oct 18;3(20):123687. doi: 10.1172/jci.insight.123687.
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.
癌症是起源细胞中遗传突变的积累所致。我们和其他人也已经表明，损伤会促进肉瘤的发生，但在肿瘤形成的最早阶段，损伤如何与遗传突变相互作用尚不清楚。在这里，我们利用双重组酶技术，在软组织肉瘤的原代小鼠模型中，剖析了 KrasG12D 激活、p53 缺失和肌肉损伤的时间在肉瘤发生中的复杂相互作用。当致癌性 Kras 和 p53 的突变相隔 3 周时，如果没有损伤，很少会发生肉瘤。然而，肌肉损伤可以揭示这些肿瘤起始细胞的转化潜能。在没有 Kras 突变的情况下，肌肉损伤导致 p53 全局缺失，导致染色体区域包含 Met 或 Yap1 基因的扩增，这些区域发生肉瘤。这些发现表明遗传突变的时间和肿瘤微环境的干扰之间存在复杂的相互作用，这为肉瘤发生的最早阶段提供了深入了解。
