Notch Signaling Suppresses Melanoma Tumor Development in BRAF/Pten Mice

Simple Summary It is now well recognized that alterations in both oncogenic and tumor suppressor genes are required for cutaneous melanoma tumorigenesis. Although Notch signaling has been implicated in many aspects of melanoma biology, the exact role Notch genes play in melanomagenesis is not completely understood. Employing BRAF(CA)/Pten(-/-) mice, a widely used genetic mouse model of melanoma, we set out to investigate the role of Notch genes in melanomagenesis. Furthermore, using a quantitative immunohistochemical analysis of a clinically annotated human primary melanoma tissue microarray, we asked whether the amount of NOTCH proteins present in the tumor correlate with the aggressiveness of the tumor as measured by the development of metastatic disease in patients. Our data show that Notch1 and Notch2 genes do not function as tumor suppressor genes, unlike Pten, i. e., the loss of Notch1 or Notch 2 or both fail to induce melanoma in BRAF(CA) mice. However, the loss of Notch1 or Notch2 accelerated melanomagenesis. Once the melanoma tumor is initiated, the amount of NOTCH protein expressed in human melanoma does not appear to reliably predict melanoma aggressiveness. Therefore, identifying and targeting signaling pathways regulated by Notch may be a useful strategy for melanoma prevention. Both oncogenic and tumor suppressor roles have been assigned to Notch signaling in melanoma. In clinical trials, Notch inhibitors proved to be ineffective for melanoma treatment. Notch signaling has also been implicated in melanoma transdifferentiation, a prognostic feature in primary melanoma. In this study, we investigated the role of Notch signaling in melanoma tumor development and growth using the genetic model of mouse melanoma by crossing BRAF(CA/+)/Pten(+/+)/Tyr-CreER+ (B) and BRAF(CA/+)/Pten(-/-)/Tyr-CreER + (BP) mice with Notch1 or Notch2 floxed allele mice. The topical application of tamoxifen induced tumors in BP mice but not in B mice with or without the deletion of either Notch1 or Notch2. These data show that the loss of either Notch1 nor Notch2 can substitute the tumor suppressor function of Pten in BRAFV600E-induced melanomagenesis. However, in Pten-null background, the loss of either Notch1 or Notch2 appeared to accelerate BRAFV600E-induced tumor development, suggesting a tumor suppressor role for Notch1 and Notch2 in BRAFV600E/Pten-null driven melanomagenesis. Quantitative immunochemical analysis of a human cutaneous melanoma tissue microarray that consists of >100 primary tumors with complete clinical history showed a weak to moderate correlation between NOTCH protein levels and clinical and pathological parameters. Our data show that Notch signaling is involved during melanomagenesis and suggest that the identification of genes and signaling pathways downstream of Notch could help devise strategies for melanoma prevention.

Automated summary

Both oncogenic and tumor suppressor roles have been assigned to Notch signaling in melanoma. In clinical trials, Notch inhibitors proved to be ineffective for melanoma treatment. Notch signaling has also been implicated in melanoma transdifferentiation, a prognostic feature in primary melanoma. Our study investigated the role of Notch signaling in melanoma tumor development and growth using a genetic mouse model and found that the loss of Notch1 or Notch2 can substitute the tumor suppressor function of Pten in melanomagenesis. However, the loss of Notch1 or Notch2 may accelerate tumor development in the absence of Pten, suggesting a tumor suppressor role for Notch1 and Notch2 in melanomagenesis. Additionally, our data show that NOTCH protein levels in human melanoma do not reliably predict melanoma aggressiveness.