Abstract Number: 13

Intrapatient evolution of melanoma

C. Fedele, S. Boyle, M. Shackleton

Meeting: 2014 Dermcoll

Session Information

Date: -

Session Title: Melanoma Symposium 1

Session Time: -

Following cancer formation, disease progression is often driven by additional genetic changes that enable Darwinian-style selection of more aggressive clones – a process called clonal evolution – that subsequently dominate a patient’s disease burden. Understanding how this occurs and how to counter evolutionary change in cancer are high priorities in cancer research. In preliminary work, we have found that high proportions (∼70%) of tumorigenic melanoma cells can generate striking molecular diversity within tumors. This is potent fuel for evolutionary adaptation in this disease and raises the fundamental question as to thus whether, during evolution, melanomas have large or only limited potentials to hijack a variety of molecular mechanisms for promoting tumor progression. Indeed, although adaptive evolution during BRAF-targeted therapy mostly converges on (MAPK) pathway reactivation, it is poorly understood if and/or how melanomas evolve without the selective pressure imposed by therapy, and, if so, whether many or only a few molecular signalling pathways are involved. Addressing these questions and elucidating those pathways will be critical to increasing cancer cure rates.
Accordingly, we have identified a convergent evolutionary trajectory taken by progressing melanomas in the absence of therapy. In high proportions of patient and patientderived xenografted (PDX) melanomas in NSG mice, we have observed consistent changes in melanomas during disease progression, characterized by increased tumor aggressiveness and de-differentiation phenotypes. Genotyping of tumors suggests classical clonal evolution as the basis for the changes, which are associated with downregulated molecular signalling of specific pathways. These data contrast with epigenetically based models of melanoma progression that propose plastic interconversion among melanoma cells between states of more and less melanocytic differentiation, or the unidirectional generation in melanomas of more differentiated and less tumorigenic cells from cancer stem cell sub-populations.