Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines
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Updated: Oct 17, 2026
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
1Department of Dermatology, Massachusetts General Hospital and Dana-Farber/Partners CancerCare, Boston 02114, USA.
Abstract:
Both inactivation of the tumor suppressor gene, PTEN/MMAC1, and oncogenic activation of RAS have been described in human cutaneous melanoma. In mice, activation of a RAS-containing pathway is a necessary step in the pathogenesis of murine melanomas. Because PTEN negatively regulates on the downstream effects of phosphatidylinositol-3-kinase (PI3-K), we hypothesized that the loss of PTEN/MMAC1 and the activation of RAS may be largely equivalent because RAS is a known positive upstream regulator of PI3-K. We expanded our previous survey of PTEN/MMAC1 mutations and analyzed the RAS status of 53 cutaneous melanoma cell lines, 18 glioma cell lines, and 17 uncultured cutaneous melanoma metastasis. Overall, 51% of the cell lines had alterations in either PTEN/MMAC1 or RAS. We found 16 cell lines (30%) with alterations in PTEN/MMAC1 and 11 cell lines (21%) with activating NRAS mutations; only 1 cell line had concurrent alterations in both genes. Moreover, glioma cell lines with a high frequency of PTEN/MMAC1 inactivation had no identifiable RAS alterations. Ectopic expression of PTEN in several cutaneous melanoma cell lines suppressed colony formation irrespective of PTEN/MMAC1 status; furthermore, PTEN expression in cell lines carrying activated RAS also suppressed colony formation. The relative reciprocity of PTEN/MMAC1 abrogation and NRAS activation suggests that the two genetic changes, in a subset of cutaneous melanomas, are functionally overlapping.
Insights
Loss of the PTEN/MMAC1 tumor suppressor gene and activation of RAS signaling are common in melanoma. These genetic changes appear functionally overlapping, suggesting they can act similarly in melanoma development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- PTEN/MMAC1 inactivation and RAS activation are implicated in human cutaneous melanoma.
- RAS pathway activation is crucial for murine melanoma development.
- PTEN negatively regulates phosphatidylinositol-3-kinase (PI3-K) signaling.
Purpose of the Study:
- To investigate the relationship between PTEN/MMAC1 and RAS alterations in melanoma.
- To determine if PTEN/MMAC1 loss and RAS activation are functionally equivalent in melanoma pathogenesis.
Main Methods:
- Analysis of PTEN/MMAC1 mutations and RAS status in 53 cutaneous melanoma cell lines, 18 glioma cell lines, and 17 uncultured melanoma metastases.
- Ectopic expression of PTEN in melanoma cell lines to assess its effect on colony formation.
- Correlation analysis of genetic alterations and gene expression patterns.
Main Results:
- 51% of analyzed cell lines exhibited alterations in either PTEN/MMAC1 or RAS.
- 16 cell lines (30%) had PTEN/MMAC1 alterations, and 11 (21%) had activating NRAS mutations.
- PTEN re-expression suppressed colony formation, regardless of PTEN/MMAC1 status or RAS activation, indicating functional overlap.
Conclusions:
- PTEN/MMAC1 abrogation and NRAS activation are functionally overlapping genetic events in a subset of cutaneous melanomas.
- These findings suggest that targeting the PI3-K pathway could be a therapeutic strategy for melanomas with either PTEN/MMAC1 or RAS alterations.
- Glioma cell lines showed high PTEN/MMAC1 inactivation but no RAS alterations, suggesting distinct roles in different cancers.
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