Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA.
McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA.
Sci Rep. 2024 Sep 19;14(1):21915. doi: 10.1038/s41598-024-72255-9.
Therapy targeting the BRAF-MEK cascade created a treatment revolution for patients with BRAF mutant advanced melanoma. Unfortunately, 80% patients treated will progress by 5 years follow-up. Thus, it is imperative we study mechanisms of melanoma progression and therapeutic resistance. We created a scRNA (single cell RNA) atlas of 128,230 cells from 18 tumors across the treatment spectrum, discovering melanoma cells clustered strongly by transcriptome profiles of patients of origins. Our cell-level investigation revealed gains of 1q and 7q as likely early clonal events in metastatic melanomas. By comparing patient tumors and their derivative cell lines, we observed that PD1 responsive tumor fraction disappears when cells are propagated in vitro. We further established three anti-BRAF-MEK treatment resistant cell lines using three BRAF mutant tumors. ALDOA and PGK1 were found to be highly expressed in treatment resistant cell populations and metformin was effective in targeting the resistant cells. Our study suggests that the investigation of patient tumors and their derivative lines is essential for understanding disease progression, treatment response and resistance.
针对 BRAF-MEK 级联的治疗为 BRAF 突变型晚期黑色素瘤患者带来了治疗革命。不幸的是，80%接受治疗的患者在 5 年随访时会进展。因此，我们必须研究黑色素瘤进展和治疗耐药的机制。我们创建了一个包含 18 个肿瘤的 128230 个细胞的 scRNA（单细胞 RNA）图谱，发现黑色素瘤细胞根据患者起源的转录组图谱强烈聚类。我们的细胞水平研究揭示了 1q 和 7q 的获得可能是转移性黑色素瘤中的早期克隆事件。通过比较患者肿瘤及其衍生的细胞系，我们观察到当细胞在体外增殖时，对 PD1 有反应的肿瘤分数消失了。我们使用三个 BRAF 突变肿瘤进一步建立了三个抗 BRAF-MEK 治疗耐药细胞系。在耐药细胞群中发现 ALDOA 和 PGK1 高度表达，二甲双胍能有效靶向耐药细胞。我们的研究表明，对患者肿瘤及其衍生系的研究对于理解疾病进展、治疗反应和耐药性至关重要。
