We have observed a pervasive potential among melanoma cells to acquire new mutations during disease progression. Although this predicts that melanomas may follow a multitude of evolutionary trajectories, particularly in the absence of treatment, this has not been tested.
To identify evolutionary trajectories in melanoma, we evaluated biopsies removed serially from patients. In fractional sampling of metastatic disease, >20% of pigmented primary melanomas seeded metastases that were amelanotic, indicating that melanoma progression is linked to melanocytic de-differentiation in some patients. Consistent with this, positron emission tomography (PET) revealed 7/10 melanoma patients with FDG-PET positive metastatic disease that did not bind the melanin-binding tracer MEL050.
Heritable de-differentiation phenotypes were also evident sub-clonally during early passaging of 13/17 patient-derived xenografted (PDX) melanomas. Evolved non-pigmented sub-clones were less necrotic, more vascular and more proliferative than pigmented sub-clones in the same tumor, in line with selection of more aggressive disease. Genetic differences between pigmented and non-pigmented sibling sub-clones indicated clonal evolution of more aggressive, de-differentiated disease.
These data suggest that the classical pigment phenotype switching model, in which melanoma cells plastically revert between pigmented states associated with changing malignant behaviours, does not always apply during in vivo progression of patient-derived melanomas. Rather, melanoma progression can be driven by acquisition of new genetic changes that drive heritable loss of melanin-production and increasing tumorigenicity.
Despite the vast potential of melanoma cells to generate genetic diversity in tumors, we find that evolution during therapy-naïve disease progression in many patients converges on shared mechanisms linked to melanocytic de-differentiation, providing opportunities for improved prognostication and therapeutic targeting in early stage and loco-regional disease.