Wnt signaling in senescence, nevogenesis and melanomagenesis

In 2010 in the US, there were approximately 68,000 new cases of melanoma and about 8,700 deaths from this disease (www.cancer.org). In the UK, the incidence of melanoma has increased more than any other cancer in the last 25 years (http://www.cancerhelp.org.uk/).

Despite recent advances in targeted melanoma therapies (for example, vemurafenib) the prognosis for advanced melanoma remains dismal. The new generation of targeted therapies provide a significant, but modest, prolonged survival. However, drug resistance and disease progression invariably occurs. Consequently, there is an urgent need for better ways to combat this disease, perhaps focused on much earlier risk assessment and chemoprevention.

Melanoma results from transformation and uncontrolled growth of melanocytes, pigment producing cells in the skin, hair and eyes. The earliest apparent melanocytic neoplasms are normal benign nevi (moles), which result from clonal proliferative expansion of oncogene-expressing melanocytes in the skin.

Although the vast majority of benign human nevi do not progress to melanoma, approximately 25% of melanoma are thought to result from a pre-existing nevus. Understanding the progression of nevi to melanoma is critical to understanding the origins of melanoma.

Most nevi are thought to be prevented from progression to melanoma by a process called cellular senescence - an irreversible proliferation arrest that prevents proliferation of potentially cancerous cells.

In this application, we will better define the molecular status of nevus melanocytes. By doing so, we will inform on the origins of melanoma, whether from nevus or non-nevus melanocytes.

This application can lead to biomarkers for melanoma risk assessment in nevi and strategies for melanoma chemoprevention. For example, one minimally invasive approach to reduce incidence of melanoma in later life might be local topical application of specific inhibitors to developing nevi in childhood and adolescence, when most acquired nevi form.

Senescence is an irreversible proliferation arrest that is activated by various molecular triggers, including activation of proto-oncogenes, such as BRAF and N-Ras, in primary human cells.

Like melanoma, virtually all benign human nevi harbor activating mutations in N-RAS or its downstream effector, BRAF. But, typically, benign nevi do not progress to melanoma. At least in part, this is because cellular senescence blocks proliferation of the nevus melanocytes.

In the canonical Wnt signaling pathway, extracellular Wnt proteins bind to their cognate transmembrane receptors. Binding of Wnt to its receptor indirectly stabilizes beta-catenin, which then acts in the nucleus, in a complex with one of a family of heterodimeric binding partners, TCF family members, to drive expression of proliferative genes, such as c-myc and cyclin D1. Activated Wnt signalling promotes early stages of melanomagenesis by virtue of its ability to abrogate melanocyte senescence.

In light of the above, we and others have been surprised to find that benign human nevi express activated beta-catenin and proliferation-promoting Wnt targets, such as cyclin D1, c-myc and MITF. This would be expected to antagonize stable senescence-associated proliferation arrest.

To reconcile these observations, we have initiated a deeper analysis of the role of Wnt signaling in cell senescence, nevogenesis and melanomagenesis. We hypothesize that during nevogenesis, melanocyte proliferation and nevus formation depends on a sufficient level of Wnt signalling activity that is appropriately targeted to proliferation-promoting Wnt target genes. Since activated Wnt signalling in human nevi is expected to antagonize senescence-associated tumor suppression, we also predict that inhibition of Wnt signalling will suppress nevus to melanoma transformation.

This application can lead to biomarkers for melanoma risk assessment in nevi and strategies for melanoma chemoprevention.

The main beneficiaries of the proposed research include the general scientific community, the commercial pharmaceutical and drug development industry and, ultimately, the general public.

These groups will benefit as follows:

The general scientific community will benefit from an enhanced understanding of senescence-mediated tumor suppression, tumorigenesis, genome instability, PTEN. This group will realize the benefit from the research within the timescale of the research and shortly afterwards (3-5 years from the start of funding). The benefit will be ongoing thereafter.

The commercial pharmaceutical industry will benefit from an improved understanding of the mechanisms of nevogenesis and melanomagenesis. Benign human nevi contain oncogene-expressing senescent melanocytes. Benign human nevi also harbor activated Wnt signalling. Activated Wnt signalling tends to bypass senescence. Therefore, nevi are likely predisposed to melanoma, albeit it a very low level, but perhaps contributing to their recognized risk for melanoma. This application investigates the role of Wnt signalling in senescence, nevogenesis and melanomagenesis. This application can lead to: a) biomarkers for melanoma risk assessment in nevi; b) strategies for melanoma chemoprevention. For example, one minimally invasive approach to reduce incidence of melanoma in later life might be local topical application of Wnt inhibitors to developing nevi in childhood and adolescence, when most acquired nevi form. Hence, this project will facilitate their rational selection of targets for anti-melanoma drug development. This group will begin to see the benefit of the research from the time of publication, or before if information is released earlier to interested parties. Information might be released prior to publication as part of a focussed drug target identification/discovery collaboration. The benefit to the industry will be ongoing thereafter.

Despite recent advances in targeted melanoma therapies (for example, vemurafenib) the prognosis for advanced melanoma remains dismal. The new generation of targeted therapies provide a significant, but modest, prolonged survival. However, drug resistance and disease progression invariably occurs. Consequently, there is an urgent need for better ways to combat this disease, perhaps focused on much earlier risk assessment and chemoprevention. This application can ultimately lead to strategies for better risk assessment and chemoprevention, with a focus on the Wnt signaling pathway (a pathway of substantial drug development efforts already).

In the long term, the wider general public will benefit from the enhanced drug target identification and development process (see above). This benefit will come from rational target selection by drug companies and, perhaps, anti-melanoma drugs aimed at chemoprevention, rather than treatment of notoriously difficult to treat melanoma.

Post-doctoral and technical staff working on the project will acquire technical research skills of use in the academic or corporate research and development industries. In addition, these staff will acquire skills in multitasking, project management, report writing and data communication.