Department of Gynecologic Oncology and Reproductive Medicine, Unit 1362, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
Departments of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Sci Rep. 2020 Nov 26;10(1):20678. doi: 10.1038/s41598-020-77666-y.
How different KRAS variants impact tumor initiation and progression in vivo has not been thoroughly examined. We hypothesize that the ability of either KRAS or KRAS mutations to initiate tumor formation is context dependent. Amhr2-Cre mice express Cre recombinase in tissues that develop into the fallopian tubes, uterus, and ovaries. We used these mice to conditionally express either the KRAS or KRAS mutation. Mice with the genotype Amhr2-Cre Pten Kras(G12D mice) had abnormal follicle structures and developed low-grade serous ovarian carcinomas with 100% penetrance within 18 weeks. In contrast, mice with the genotype Amhr2-Cre Pten Kras (G12V mice) had normal follicle structures, and about 90% of them developed uterine tumors with diverse histological features resembling those of leiomyoma and leiomyosarcoma. Granulosa cell tumors also developed in G12V mice. Differences in cell-signaling pathways in the uterine tissues of G12D and G12V mice were identified using RNA sequencing and reverse-phase protein array analyses. We found that CTNNB1, IL1A, IL1B, TNF, TGFB1, APP, and IL6 had the higher activity in G12V mice than in G12D mice. These mouse models will be useful for studying the differences in signaling pathways driven by Kras or Kras mutations to aid development of targeted therapies for specific KRAS mutant variants. Our leiomyoma model driven by the Kras mutation will also be useful in deciphering the malignant progression from leiomyoma to leiomyosarcoma.
KRAS 变异体如何影响体内肿瘤的发生和进展尚未得到彻底研究。我们假设，无论是 KRAS 还是 KRAS 突变，其启动肿瘤形成的能力都是依赖于环境的。Amhr2-Cre 小鼠在发育成输卵管、子宫和卵巢的组织中表达 Cre 重组酶。我们利用这些小鼠来条件性表达 KRAS 或 KRAS 突变。基因型为 Amhr2-Cre Pten Kras(G12D 小鼠)的小鼠具有异常的卵泡结构，并在 18 周内 100%出现低级别浆液性卵巢癌。相比之下，基因型为 Amhr2-Cre Pten Kras (G12V 小鼠)的小鼠具有正常的卵泡结构，其中约 90%的小鼠发展为具有多种组织学特征的子宫肿瘤，类似于平滑肌瘤和平滑肌肉瘤。G12V 小鼠也发生了颗粒细胞瘤。通过 RNA 测序和反相蛋白阵列分析，鉴定了 G12D 和 G12V 小鼠子宫组织中细胞信号通路的差异。我们发现 CTNNB1、IL1A、IL1B、TNF、TGFB1、APP 和 IL6 在 G12V 小鼠中的活性高于 G12D 小鼠。这些小鼠模型将有助于研究由 Kras 或 Kras 突变驱动的信号通路差异，以帮助开发针对特定 KRAS 突变变体的靶向治疗方法。我们由 Kras 突变驱动的平滑肌瘤模型也将有助于解析从平滑肌瘤到平滑肌肉瘤的恶性进展。
