Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis

Abstract

Melanoma displays frequent activation of RAS/RAF/MAPK and PI3K/AKT signaling pathways as well as inactivation of CDKN2A (INK4a/ARF) and PTEN tumor suppressors via genetic and epigenetic alterations. Pathogenetic roles of these melanoma-prone mutations and their genetic interactions have been established in genetically engineered mouse models. Here, we catalog frequent genetic alterations observed in human melanomas and describe mouse models of melanoma initiation and progression, including our recent study that investigated the genetic interactions of RAS activation and PTEN loss in a CDKN2A (INK4a/ARF) null melanoma prone genetic background. We showed that loss of PTEN cooperates with HRAS activation, leading to increased development of melanoma and emergence of metastasis. Moreover, we observed that RNAi-mediated PTEN inactivation in RAS-driven melanomas enhanced migration and invasion with concomitant down-regulation of E-cadherin, the major regulator of epithelial and mesenchymal transition, and enhanced AKT2 phosphorylation, which has been previously linked to invasion and metastasis of several cancer types, including breast and ovary. These data show that activated RAS cooperates with PTEN loss in melanoma genesis and progression.

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Acknowledgements

M. Kim is supported by Melanoma Research Foundation, the Bankhead Coley Melanoma Pre-Spore, and American Cancer Society Institutional Research Grant (#93-032-13). We thank Dr. Keiran Smalley for critical reading of this manuscript and Rasa Hamilton for editorial assistance.

Figures and Tables

Figure 1 Schematic model for the cooperative interactions of PTEN deficiency and RAS activation. (A) Activated RAS (RAS*) causes RAF/MAPK activation and PI3K/AKT activation, increasing pAKT1 and 3 preferentially. (B) PTEN inactivation and RAS activation cooperates to increase pAKT2 along with pAKT1 and pAKT3.

Table 1 Top 5 genes mutated in malignant melanoma

Extra View to: Nogueira C, Kim KH, Sung H, Paraiso K, Dannenberg JH, Bosenberg M, et al. Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis. Oncogene 29:6222 - 6232; PMID: 20711233; http://dx.doi.org/10.1038/onc.2010.349

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