Cellular and molecular pathways regulating melanoma genesis and progression

Melanoma is a deadly, highly metastatic cancer, whose incidence has dramatically increased. Although melanoma is curable when detected early, metastatic disease causes the death of the majority of patients. None of the current systemic treatment options has produced long-term control of the disease except on rare occasions. These findings underscore the need for increasing our knowledge of the underlying causes of melanoma development and progression, in order to build up better therapeutic strategies.

On the genetic level, the characteristic events for melanoma are activating mutations of B-Raf or Ras and functional loss of PTEN and of the INK4a/Arf locus encoding tumor suppressors, p16 and Arf, whose expression enhances the growth suppressive functions of Rb and p53, respectively. These mutations and deletions have been found in all the different stages of melanoma progression. However, genetic events associated with melanoma progression and metastasis formation have not been clearly and unambiguously identified.

The critical factor in the metastatic spread of melanomas is represented by the acquired ability of melanoma cells to survive in the dermis. The survival and the subsequent migration properties seem to be dependent on "de novo" interaction of melanoma cells with components of the extracellular matrix and dermal cell types, due to altered expression of adhesion molecules and growth factor receptors.

The main interest of this unit is the understanding of the cellular and molecular pathways involved in melanoma genesis and progression. We have recently identified and structurally characterized a new member of the Shc family of adaptor proteins (RaLP), whose expression is confined to the cells of melanocytic origin, and is critical for melanoma invasion and metastasis. Genetic and biological evidence indicates that the mammalian Shc proteins regulate functions as diverse as growth (p52/p46Shc), apoptotic signals (p66Shc), life-span (p66Shc) and survival (p52Rai). The biological function of RaLP in cells of melanocytic origin and its role in melanogenesis is being investigated by three different approaches:

1) set up of primary cultures of melanoblasts, melanocytes and melanoma cells (Fig. 2) that will recapitulate melanoma formation and progression in vitro. This tool will allow the genetic manipulation of cells at different stages of differentiation and transformation to investigate which are the pathways involved in the pathogenesis and progression to metastasis of the melanoma. Attention will be dedicated to the role of RaLP in cell migration and proliferation.
2) Generation of appropriate mouse models of melanomas. A mouse model of RaLP KO is already available in the laboratory, while RaLP overexpressing mice will be generated by inserting the murine RaLP cDNA into the HPRT locus. The in vivo approach will be useful to dissect the role of RaLP during embryogenesis.
3) Identification and biological characterization of normal and cancer melanocytic stem cells. Melanocyte stem cells have been found in the hair bulge of the skin of adult mice. A line of research will be aimed at analysing the influence of this new transducer on parameters of staminality.

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4)Tbx3 represses E-cadherin expression and enhances melanoma invasiveness.
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6)Patrussi L, Ulivieri C, Lucherini OM, Paccani SR, Gamberucci A, Lanfrancone L, Pelicci PG, Baldari CT. p52Shc is required for CXCR4-dependent signaling and chemotaxis in T cells.
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7)Fagiani E, Giardina G, Luzi L, Cesaroni M, Quarto M, Capra M, Germano G, Bono M, Capillo M, Pelicci P, Lanfrancone L. RaLP, a new member of the Src homology and collagen family, regulates cell migration and tumor growth of metastatic melanomas. Cancer Res. 2007 Apr 1;67(7):3064-73.

8)Graiani G, Lagrasta C, Migliaccio E, Spillmann F, Meloni M, Madeddu P, Quaini F, Padura IM, Lanfrancone L, Pelicci P, Emanueli C. Genetic deletion of the p66Shc adaptor protein protects from angiotensin II-induced myocardial damage.
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9)Patrussi L, Savino MT, Pellegrini M, Paccani SR, Migliaccio E, Plyte S, Lanfrancone L, Pelicci PG, Baldari CT. Cooperation and selectivity of the two Grb2 binding sites of p52Shc in T-cell antigen receptor signaling to Ras family GTPases and Myc-dependent survival.
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No projects are available to students for the current accademic year.