Last week’s issue of Cell contained a very interesting paper that used comparisons of a variety of human cancer genomes to identify a novel promoter of metastasis in melanomas – Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene.
As Kim et al. note, “Recurrent chromosomal structural aberrations are a hallmark feature of the human cancer genome and represent key pathogenetic events required for malignant transformation (Hanahan & Weinberg, 2000; Storchova & Pellman, 2004). The high resoluiton views afforded by current genome scanning platforms, such as array-Comparative Genomic Hybridization (CGH), has revealed presence of hundreds of recurrent focal copy number alterations (CNAs),” which may aid in identifying genes of primary pathological significance.
These genomic characterizations have defined many minimal regions of recurring chromosomal aberrations associated with cancer progressions, which they describe as “focal minimal common regions,” or MCRs. Using an inducible genetically-engineered mouse model for melanoma, Kim et al. generated a series of 17 tumor cell lines. Of these 17, two appeared to “acquire secondary genomic/genetic event(s) that conferred metastatic capability.” With these two metastatic variants, Kim et al. performed CGH profiling, identifying a focal MCR comprised of eight genes. Comparisons of expression patterns of these eight genes with other melanoma and melanocyte cell lines indicated that only Nedd9 showed consistent overexpresion.
NEDD9, an adaptor protein related to p130Cas, appears to function in much the same way as Cas, based upon their follow-up data: it required focal adhesion kinase (FAK) for its promotion of metastasis, and modulated focal adhesion formation. The implication for this protein in metastasis appears fairly straightforward, given an already well-characterized signaling pathway for Cas:
Central to the process of migration and invasion is focal adhesion kinase (FAK), a nonreceptor tyrosine kinase localized at the sites of integrin clustering and cell attachment to the extracellular matrix. The nucleation of a FAK-Cas-Crk-DOCK180 complex is the molecular signal for invasion (McLean et al. 2005).
DOCK180, in tern, is an activator of Rac1, which affects actin cytoskeleton remodeling and induces JNK activities to promote MMP expression and extracellular matrix degradation. This entire signaling pathway has been highly implicated in promoting cell migration in vitro over numerous studies in the last 10 years, and complements Ras-induced dysfunction of cell-cell contacts (the EMT phenomenon).
Further, a migrational role for NEDD9 in melanocytes makes physiological sense. NEDD9 was originally identified by its developmentally regulated expression pattern in the brain; and melanocytes are neural crest derivatives that possess the inherent ability to migrate to distant locations during development; and the link between developmental physiology and cancer pathology is a rising theme in cell biology (Gupta et al., 2005). In such a way, NEDD9 may represent yet another example of an embryonic differentiation program gone awry in cancer.
- Comparative Oncogenomics Identifies NEDD9 as a Melanoma Metastasis Gene. Kim M, Gans JD, Nogueira C, Wang A, Paik JH, Feng B, Brennan C, Hahn WC, Cordon-Cardo C, Wagner SN, Flotte TJ, Duncan LM, Granter SR, Chin L. Cell. 2006 Jun 30; 125(7):1269-81. Pubmed.
- The hallmarks of cancer. Hanahan D, Weinberg RA. Cell. 2000 Jan 7; 100(1):57-70. Pubmed.
- From polyploidy to aneuploidy, genome instability and cancer. Storchova Z, Pellman D. Nat Rev Mol Cell Biol. 2004 Jan; 5(1):45-54. Pubmed.
- The role of focal-adhesion kinase in cancer – a new therapeutic opportunity. McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC. Nat Rev Cancer. 2005 Jul; 5(7):505-15. Pubmed.
- The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Gupta PB, Kuperwasser C, Brunet JP, Ramaswamy S, Kuo WL, Gray JW, Naber SP, Weinberg RA. Nat Genet. 2005 Oct; 37(10):1047-54. Pubmed.