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Spontaneous and UV radiation-induced multiple metastatic melanomas in Cdk4R24C/R24C/TPras mice
Elke Hacker1, H Konrad Muller, Nicole Irwin
1Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Abstract:
Human melanoma susceptibility is often characterized by germ-line inactivating CDKN2A (INK4A/ARF) mutations, or mutations that activate CDK4 by preventing its binding to and inhibition by INK4A. We have previously shown that a single neonatal UV radiation (UVR) dose delivered to mice that carry melanocyte-specific activation of Hras (TPras) increases melanoma penetrance from 0% to 57%. Here, we report that activated Cdk4 cooperates with activated Hras to enhance susceptibility to melanoma in mice. Whereas UVR treatment failed to induce melanomas in Cdk4(R24C/R24C) mice, it greatly increased the penetrance and decreased the age of onset of melanoma development in Cdk4(R24C/R24C)/TPras animals compared with TPras alone. This increased penetrance was dependent on the threshold of Cdk4 activation as Cdk4(R24C/+)/TPras animals did not show an increase in UVR-induced melanoma penetrance compared with TPras alone. In addition, Cdk4(R24C/R24C)/TPras mice invariably developed multiple lesions, which occurred rarely in TPras mice. These results indicate that germ-line defects abrogating the pRb pathway may enhance UVR-induced melanoma. TPras and Cdk4(R24C/R24C)/TPras tumors were comparable histopathologically but the latter were larger and more aggressive and cultured cells derived from such melanomas were also larger and had higher levels of nuclear atypia. Moreover, the melanomas in Cdk4(R24C/R24C)/TPras mice, but not in TPras mice, readily metastasized to regional lymph nodes. Thus, it seems that in the mouse, Hras activation initiates UVR-induced melanoma development whereas the cell cycle defect introduced by mutant Cdk4 contributes to tumor progression, producing more aggressive, metastatic tumors.
Insights
Neonatal UV radiation exposure combined with activated Hras and Cdk4 significantly increases melanoma development and aggressiveness in mice. This suggests germline defects in the pRb pathway may enhance UV-induced melanoma risk.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Human melanoma is linked to CDKN2A mutations or CDK4 activation.
- UV radiation (UVR) is a known melanoma risk factor.
- Previous studies showed UVR increases melanoma in mice with melanocyte-specific Hras activation (TPras).
Purpose of the Study:
- To investigate the cooperative effect of activated Cdk4 and activated Hras on melanoma susceptibility in mice.
- To determine if germline defects abrogating the pRb pathway enhance UVR-induced melanoma.
Main Methods:
- Utilized genetically engineered mouse models with melanocyte-specific Hras activation (TPras) and varying Cdk4 activation levels (Cdk4(R24C/R24C) and Cdk4(R24C/+)).
- Administered a single neonatal UV radiation (UVR) dose to assess melanoma development and progression.
- Compared melanoma penetrance, age of onset, tumor characteristics, and metastatic potential across different genotypes.
Main Results:
- UVR failed to induce melanoma in Cdk4(R24C/R24C) mice but significantly increased melanoma penetrance and decreased onset age in Cdk4(R24C/R24C)/TPras mice compared to TPras alone.
- Increased melanoma penetrance was dependent on the threshold of Cdk4 activation.
- Cdk4(R24C/R24C)/TPras mice developed larger, more aggressive melanomas with higher nuclear atypia and readily metastasized to lymph nodes.
- Melanomas in TPras mice were histopathologically similar but less aggressive and non-metastatic.
Conclusions:
- Activated Cdk4 cooperates with activated Hras to enhance susceptibility to UVR-induced melanoma in mice.
- Germline defects abrogating the pRb pathway, such as Cdk4 activation, can enhance UVR-induced melanoma development and progression.
- Hras activation initiates UVR-induced melanoma, while Cdk4 activation drives tumor progression towards more aggressive, metastatic disease.
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