Differences in gynecologic tumor development in Amhr2-Cre mice with KRASG12D or KRASG12V mutations
Eucharist H S Kun1, Yvonne T M Tsang1, Sophia Lin1
1Department of Gynecologic Oncology and Reproductive Medicine, Unit 1362, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
Abstract:
How different KRAS variants impact tumor initiation and progression in vivo has not been thoroughly examined. We hypothesize that the ability of either KRASG12D or KRASG12V 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 KRASG12V/+ or KRASG12D/+ mutation. Mice with the genotype Amhr2-Cre Pten(fl/fl) KrasG12D/+(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(fl/fl) KrasG12V/+ (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 KrasG12V/+ or KrasG12D/+ mutations to aid development of targeted therapies for specific KRAS mutant variants. Our leiomyoma model driven by the KrasG12V/+ mutation will also be useful in deciphering the malignant progression from leiomyoma to leiomyosarcoma.
Insights
Different KRAS mutations initiate distinct tumors. KRAS G12D causes ovarian cancer, while KRAS G12V drives uterine tumors, offering new models for targeted therapy research.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The impact of distinct KRAS variants on tumor initiation and progression in vivo remains underexplored.
- KRAS mutations are common in human cancers, but their specific roles in tumorigenesis vary.
- Understanding context-dependent effects of KRAS mutations is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the differential effects of KRAS G12D and KRAS G12V mutations on tumor formation in vivo.
- To establish and characterize novel mouse models for studying KRAS-driven ovarian and uterine tumors.
- To identify differences in signaling pathways associated with specific KRAS variants.
Main Methods:
- Conditional expression of KRAS G12D/+ and KRAS G12V/+ mutations in Amhr2-Cre; Pten(fl/fl) mice.
- Histological analysis of tumor development and characterization.
- RNA sequencing and reverse-phase protein array (RPPA) analyses to compare signaling pathways.
Main Results:
- KRAS G12D/+ mice developed low-grade serous ovarian carcinomas with 100% penetrance.
- KRAS G12V/+ mice developed uterine tumors (leiomyoma/leiomyosarcoma) and granulosa cell tumors in approximately 90% of cases.
- Distinct signaling pathway activation was observed between G12D and G12V mouse models, with elevated activity of CTNNB1, IL1A, IL1B, TNF, TGFB1, APP, and IL6 in G12V mice.
Conclusions:
- KRAS G12D and KRAS G12V mutations exhibit distinct tissue-specific tumor-initiating capabilities and progression patterns.
- The developed mouse models accurately recapitulate human ovarian and uterine tumors driven by specific KRAS variants.
- These models provide valuable platforms for dissecting KRAS-driven signaling pathways and advancing targeted therapeutic strategies for KRAS-mutant cancers.
Related Concept Videos
02:43Mouse Models of Cancer Study
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
02:38The Ras Gene
Ras is a...