Therapies targeting signaling molecules mutated in cancers can often have striking short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures1,2.,Resistance can result from a secondary mutations3,4, but other times there is no clear genetic cause, raising the possibility of non-genetic rare cell variability5-11.,Here, we show that melanoma cells can display profound transcriptional variability at the single cell level that predicts which cells will ultimately resist drug treatment.,This variability involves infrequent, semi-coordinated transcription of a number of resistance markers at high levels in a very small percentage of cells.,The addition of drug then induces epigenetic reprogramming in these cells, converting the transient transcriptional state to a stably resistant state.,This reprogramming begins with a loss of SOX10-mediated differentiation followed by activation of new signaling pathways, partially mediated by activity of Jun-AP-1 and TEAD.,Our work reveals the multistage nature of the acquisition of drug resistance and provides a framework for understanding resistance dynamics in single cells.,We find that other cell types also exhibit sporadic expression of many of these same marker genes, suggesting the existence of a general rare-cell expression program.
Acral melanoma (AM), as a peculiar subgroup of melanoma, is rare in Caucasians but has higher incidence in Asians.,Large series of study on AM with clinicopathological features and prognostic factors is still limited, especially in Asian population.,We retrospectively collected clinical, pathological and follow-up data of 142 AM cases.,All patients were Chinese, with the age ranging from 24 to 87 years (mean 62.0; median 62.0).,The Breslow thickness of primary lesions ranged from 0.6 to 16.3 mm (mean 4.9; median 3.7).,85.9% of the patients had acral lentiginous histologic subtype.,Plantar was the most frequently involved site, followed by heels.,Statistically, duration of the lesion before diagnosis (≤2.5 years), Breslow thickness >4.0 mm (T4), high mitotic index (>15 mm−2), presence of vascular invasion, regional lymph node metastasis at diagnosis and pathologic stage (II/III/IV) were found to be independent prognostic factors in both univariate and multivariate analyses.,The prognosis of AM in Chinese is extremely poor.,Our 5- and 10-year disease-specific survival (DSS) rates were 53.3% and 27.4%, respectively.,Therefore, AM in Asians represents a more biologically aggressive melanoma subtype and is thought to carry a worse prognosis when compared with other races or cutaneous melanomas in other anatomic sites.