Review: Are moles senescent?

Melanocytic nevi (skin moles) have been regarded as a valuable example of cell senescence occurring in vivo. However, a study of induced nevi in a mouse model reported that the nevi were arrested by cell interactions rather than a cell-autonomous process like senescence, and that size distributions of cell nests within nevi could not be accounted for by a stochastic model of oncogene-induced senescence. Moreover, others reported that some molecular markers used to identify cell senescence in human nevi are also found in melanoma cells-not senescent. It has thus been questioned whether nevi really are senescent, with potential implications for melanoma diagnosis and therapy. Here I review these areas, along with the genetic, biological, and molecular evidence supporting senescence in nevi. In conclusion, there is strong evidence that cells of acquired human benign (banal) nevi are very largely senescent, though some must contain a minor non-senescent cell subpopulation. There is also persuasive evidence that this senescence is primarily induced by dysfunctional telomeres rather than directly oncogene-induced.

RNA Therapy for Oncogenic NRAS-Driven Nevi Induces Apoptosis.

RAS proteins regulate cell division, differentiation, and apoptosis through multiple downstream effector pathways. Oncogenic RAS variants are the commonest drivers in cancers; however, they also drive many benign lesions predisposing to malignancy, such as melanocytic nevi, thyroid nodules, and colonic polyps. Reversal of these benign lesions could reduce cancer incidence; however, the effects of oncogenic RAS have been notoriously difficult to target with downstream pathway inhibitors. In this study, we show effective suppression of oncogenic and currently undruggable NRASQ61K in primary cells from melanocytic nevi using small interfering RNA targeted to the recurrent causal variant. This results in striking reduction in expression of ARL6IP1, a known inhibitor of endoplasmic reticulum stress-induced apoptosis not previously linked to NRAS. We go on to show that a single dose of small interfering RNA in primary cells triggers an apoptotic cascade, in contrast to treatment with a MAPK/extracellular signal-regulated kinase kinase inhibitor. Protective packaging of the targeted small interfering RNA into lipid nanoparticles permits successful delivery into a humanized mouse model of melanocytic nevi and results in variant NRAS knockdown in vivo. These data show that RAS-induced protection from apoptosis is involved in persistence of NRAS-driven melanocytic nevi and anticipate that targeted small interfering RNA could form the basis of clinical trials for RAS-driven benign tumors.