Absence of telomerase restricts melanoma development.

Most cancers reactivate telomerase to maintain telomere length to acquire immortality. The importance of this process is well illustrated by the fact that telomerase promoter mutations are found at a high frequency in many cancer types, including melanoma. However, it is unclear when and if telomerase is strictly required during tumorigenesis. Here we show that melanoma can occur in the absence of telomerase. Nevertheless, it is required to sustain later growth and avoid regression. Using telomerase mutant zebrafish (tert-/-) combined with two established melanoma models, we found equal melanoma incidence and invasiveness as tumors became visible. Later, however, while WT fish develop increasing larger tumors, tert-/- tumors stagnate growth and regress. Consistently, tert-/- tumors showed lower cell proliferation, higher apoptosis and melanocyte differentiation. We also detected an immune response to tert-/- tumors. Indeed, tert-/- tumors resumed growth when transplanted to immunocompromised hosts. We propose that, telomerase is required for melanoma in zebrafish, albeit at later stages of progression, to sustain growth while avoiding immune rejection and regression. Thus, absence of telomerase restricts melanoma through tumor-autonomous mechanisms (cell cycle arrest, apoptosis and melanocyte differentiation) and a non-tumor-autonomous mechanisms (immune rejection).