Table 1.
Summary of single-cell melanoma transcriptomics and proteomics studies and main outcome.
| No | Melanoma Samples | Experimental or Clinical Set-Up | Characteristics of Clonal Structure | Main Findings | References |
|---|---|---|---|---|---|
| 1. | Primary melanomas and metastases (n = 19) |
Untreated | Clonal signatures of cell cycle, spatial context, drug-resistance programs | Presence of AXL-high/MITF-low population in a AXL-low/ MITF-high cluster; single-cell signatures with prognostic relevance | [80] |
| 2. | Melanoma cell lines representing different stages of differentiation (n = 8) |
Untreated | Cell clones with SOX9 and SOX10 high expression and transitional cells, knockdown of SOX10 affects clonal structure | Transition between gene networks instead of selection of individual clones (transcriptional plasticity) | [82] |
| 3. | Melanoma short-term cultures (BRAF and/or NRAS mutant) (n = 3) |
Untreated | Clonal structure of cell cycle, stromal, OxPhos, pigmentation genes | Four different clonal structures with additional subclonal structures and stem cell-like subclones | [65] |
| 4. | Samples from 32 metastatic melanoma patients (n = 48) |
Anti-PD1 inhibitor treatment of patients, either alone or in combination with anti-CTLA4 treatment | CD8+ T cells clones consisted of memory/survival (TCF7+) and exhaustion (CD38+) clones, respectively | TCF7+/CD8+ T cells are crucial for treatment response | [83] |
| 5. | Human melanoma samples (n = 33) |
Clinical samples under anti-CTLA4 treatment | Clonal immune exclusion program: CDK4/CDK6 expression, JAK-STAT3 signaling, TNF pathway, senescence-associated programs, Myc targets | CDK4/CDK6 inhibitor treatment of resistant clones improved survival of mice in a murine melanoma model | [84] |
| 6. | Human melanoma samples (n = 25) |
Anti-PD-1 inhibitor treatment of patients, either alone or in combination with anti-CTLA4 treatment | CD4+/CD8+ T cells with clusters of resting, transitional and exhausted T cells | Dysfunctional (exhausted) CD8+ T cells are still proliferative and showed tumor reactivity ex vivo | [85] |
| 7. | Tumor tissue of melanoma cell line mouse xenografts (minimal residual disease) (n = 3) |
Murine xenograft model, BRAFi treatment | Minimal residual disease with 4 different transcriptional subpopulations (pigmented, SMC, NCSC, invasive cells) | Enrichment of neuronal stem cells population after BRAFi treatment; successful treatment with retinoid receptor inhibitor | [86] |
| 8. | A375 and 451Lu melanoma cell lines (n = 2) |
BRAFi treatment | Patterns of resistance are present in parental cells and vice versa | Identification of a pre-resistant state at the tip of the parental population | [64] |
| 9. | Melanoma cell line A375 (n = 1) |
BRAFi treatment after CRISPR/Cas interference with MAPK pathway | Clonal selection of treatment resistant clones | Resistance-mediating positions in MAPK genes were mostly located around MEK1E203K or KRASQ61 | [87] |
| 10. | BRAF-mutant melanoma cell lines (n = 3) |
BRAFi treatment; testing of 13 different proteomic markers with single-cell barcode chip technology | Increased clonal heterogeneity under treatment | Activation of MEK/ERK and NF-κB p65 signaling in resitant clones; NF-κB inhibitor increased sensitivity of cells | [88] |
| 11. | BRAF-mutant melanoma cell line (n = 1) |
BRAFi treatment; testing of 19 different proteomic markers with single-cell barcode chip technology | Drug-induced clonal cell states changes with NGFR/AXL or MITF, MART1 patterns | Two different trajectories of treatment resistance of MITF-high and MITF- low cells | [89] |
Abbreviations: BRAFi, BRAF inhibitor; SMC, starved-like melanoma cells, NCSC, neural crest stem cells; MAPK, mitogen-activated protein kinases; NGFR, nerve growth factor receptor; MITF, microphthalmia-associated transcription factor.