Abstract
A neural crest stem cell (NCSC) transcriptional state driven by RXRG underlies relapse in melanoma.
Major finding: A neural crest stem cell (NCSC) transcriptional state driven by RXRG underlies relapse in melanoma.
Approach: Single-cell RNA-seq of BRAF-mutant melanoma PDXs characterizes minimal residual disease in vivo.
Impact: Targeting RXR impairs reprogramming into the NCSC state and delays time to progression.
In patients with melanoma, therapeutic responses are often followed by relapse driven by a small subpopulation of residual or drug-tolerant cells, termed minimal residual disease (MRD). To advance the understanding of the biology of MRD, Rambow, Rogiers, and colleagues performed single-cell DNA and RNA sequencing (RNA-seq) of cells from patient-derived xenografts (PDX) derived from BRAF-mutant melanomas from patients treated with a BRAF/MEK inhibitor combination. MRD contained cells with both low and high expression of the melanoma survival oncogene MITF, expression of which had previously been linked to drug resistance. Single-cell RNA-seq uncovered multiple distinct coexisting drug-tolerant transcriptional states associated with MRD. In one of these states, characterized by high expression of neural crest stem cell (NCSC) markers, the transcriptional program was largely driven by RXRG. The NCSC population was associated with drug resistance. NCSC cells were present in low frequency in drug-naïve melanoma lesions and became more abundant during drug-induced tumor regression, even though cell proliferation is minimal in this phase. Further, the NCSC state was reversible, as drug-induced upregulation of NCSC markers was lost after drug removal, suggesting that MAPK inhibition induces a transient and reversible phenotypic switch to a quiescent NCSC state. Targeting the NCSC population with an RXR antagonist enhanced the antitumor activity of combined BRAF/MEK inhibition. Combined treatment with an RXR antagonist plus BRAF and MEK inhibitors suppressed tumor growth, delaying time-to-disease progression in a melanoma PDX model. The RXR antagonist–mediated reduction in the NCSC state was accompanied by concomitant increases in the other drug-tolerant states, providing further support for the NCSC in driving relapse. In addition to characterizing MRD in vivo, these findings suggest that therapeutic targeting of the NCSC state may suppress disease progression and therapy resistance in melanoma.
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