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[Cancer Research 65, 4005-4011, May 15, 2005]
© 2005 American Association for Cancer Research

Molecular Biology, Pathobiology, and Genetics

Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background

Julien Ackermann1, Manon Frutschi1, Kostas Kaloulis1, Thomas McKee2, Andreas Trumpp1 and Friedrich Beermann1

1 ISREC, Swiss Institute for Experimental Cancer Research, National Center of Competence in Research Molecular Oncology, Epalinges, Switzerland and 2 Institute of Pathology, University of Lausanne, Lausanne, Switzerland

Requests for reprints: Friedrich Beermann, Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland. Phone: 41-21-692-5914; Fax: 41-21-652-6933; E-mail: Friedrich.Beermann{at}isrec.ch.

In human cutaneous malignant melanoma, a predominance of activated mutations in the N-ras gene has been documented. To obtain a mouse model most closely mimicking the human disease, a transgenic mouse line was generated by targeting expression of dominant-active human N-ras (N-RasQ61K) to the melanocyte lineage by tyrosinase regulatory sequences (Tyr::N-RasQ61K). Transgenic mice show hyperpigmented skin and develop cutaneous metastasizing melanoma. Consistent with the tumor suppressor function of the INK4a locus that encodes p16INK4A and p19ARF, >90% of Tyr::N-RasQ61K INK4a–/– transgenic mice develop melanoma at 6 months. Primary melanoma tumors are melanotic, multifocal, microinvade the epidermis or epithelium of hair follicles, and disseminate as metastases to lymph nodes, lung, and liver. Primary melanoma can be transplanted s.c. in nude mice, and if injected i.v. into NOD/SCID mice colonize the lung. In addition, primary melanomas and metastases contain cells expressing the stem cell marker nestin suggesting a hierarchical structure of the tumors comprised of primitive nestin-expressing precursors and differentiated cells. In conclusion, a novel mouse model with melanotic and metastasizing melanoma was obtained by recapitulating genetic lesions frequently found in human melanoma.




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