McGrail Kimberley, Granado-Martínez Paula, Orsenigo Roberto, Caratù Ginevra, Nieto Paula, Heyn Holger, Ferrer Berta, Hernández-Losa Javier, Muñoz-Couselo Eva, García-Patos Vicenç, Recio Juan A
Biomedical Research in Melanoma-Animal Models and Cancer Laboratory-Vall d´Hebron Research Institute VHIR-Vall d'Hebron Hospital-UAB, Barcelona, Spain.
Single Cell Genomics Group at the Spanish National Centre for Genomic Analysis (CNAG), Barcelona, Spain.
Oncogene. 2025 Jun;44(21):1592-1608. doi: 10.1038/s41388-025-03339-7. Epub 2025 Mar 8.
The mechanisms behind UVB-initiated, neonatal-specific melanoma linked to BRAF are not well understood, particularly regarding its role in growth arrest. We found that, beyond mutations, neonatal UV irradiation or Lkb1 loss promotes a cell-autonomous transcriptional reprogramming that prevents BRAF-induced growth arrest, leading to melanoma development. Using UVB-dependent and independent mouse models, genomic analyses, clinical data, and single-cell transcriptomics, we identified a transcriptional program that bypasses growth arrest, promoting melanoma. In humans, many of these genes are linked to poor survival and are upregulated in melanoma progression and other RAS pathway-driven tumors. Reconstitution experiments showed these genes cooperate with BRAF in melanocyte transformation, dedifferentiation, and drug resistance. Depleting gene products like UPP1 highlights their potential as therapeutic targets. Our findings reveal that BRAF-mutated melanomas can develop independently of nevus progression and identify novel targets for treatment.
与BRAF相关的紫外线B（UVB）引发的新生儿特异性黑色素瘤背后的机制尚未完全了解，尤其是其在生长停滞中的作用。我们发现，除了突变之外，新生儿紫外线照射或Lkb1缺失会促进细胞自主性转录重编程，从而阻止BRAF诱导的生长停滞，导致黑色素瘤的发生。利用依赖UVB和不依赖UVB的小鼠模型、基因组分析、临床数据和单细胞转录组学，我们确定了一个绕过生长停滞、促进黑色素瘤发生的转录程序。在人类中，这些基因中的许多与生存率低相关，并且在黑色素瘤进展和其他RAS途径驱动的肿瘤中上调。重组实验表明，这些基因在黑素细胞转化、去分化和耐药性方面与BRAF协同作用。耗尽UPP1等基因产物凸显了它们作为治疗靶点的潜力。我们的研究结果表明，BRAF突变的黑色素瘤可以独立于痣的进展而发生，并确定了新的治疗靶点。
