Kuras Magdalena, Betancourt Lazaro Hiram, Hong Runyu, Szadai Leticia, Rodriguez Jimmy, Horvatovich Peter, Pla Indira, Eriksson Jonatan, Szeitz Beáta, Deszcz Bartłomiej, Welinder Charlotte, Sugihara Yutaka, Ekedahl Henrik, Baldetorp Bo, Ingvar Christian, Lundgren Lotta, Lindberg Henrik, Oskolas Henriett, Horvath Zsolt, Rezeli Melinda, Gil Jeovanis, Appelqvist Roger, Kemény Lajos V, Malm Johan, Sanchez Aniel, Szasz Attila Marcell, Pawłowski Krzysztof, Wieslander Elisabet, Fenyö David, Nemeth Istvan Balazs, Marko-Varga György
Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, 214 28 Malmö, Sweden.
Department of Biomedical Engineering, Lund University, 221 00 Lund, Sweden.
Cancers (Basel). 2025 Feb 27;17(5):832. doi: 10.3390/cancers17050832.
Melanoma is a highly heterogeneous disease, and a deeper molecular classification is essential for improving patient stratification and treatment approaches. Here, we describe the histopathology-driven proteogenomic landscape of 142 treatment-naïve metastatic melanoma samples to uncover molecular subtypes and clinically relevant biomarkers.
We performed an integrative proteogenomic analysis to identify proteomic subtypes, assess the impact of BRAF V600 mutations, and study the molecular profiles and cellular composition of the tumor microenvironment. Clinical and histopathological data were used to support findings related to tissue morphology, disease progression, and patient outcomes.
Our analysis revealed five distinct proteomic subtypes that integrate immune and stromal microenvironment components and correlate with clinical and histopathological parameters. We demonstrated that BRAF V600-mutated melanomas exhibit biological heterogeneity, where an oncogene-induced senescence-like phenotype is associated with improved survival. This led to a proposed mortality risk-based stratification that may contribute to more personalized treatment strategies. Furthermore, tumor microenvironment composition strongly correlated with disease progression and patient outcomes, highlighting a histopathological connective tissue-to-tumor ratio assessment as a potential decision-making tool. We identified a melanoma-associated SAAV signature linked to extracellular matrix remodeling and SAAV-derived neoantigens as potential targets for anti-tumor immune responses.
This study provides a comprehensive stratification of metastatic melanoma, integrating proteogenomic insights with histopathological features. The findings may aid in the development of tailored diagnostic and therapeutic strategies, improving patient management and outcomes.
黑色素瘤是一种高度异质性疾病，更深入的分子分类对于改善患者分层和治疗方法至关重要。在此，我们描述了142例未经治疗的转移性黑色素瘤样本的组织病理学驱动的蛋白质基因组图谱，以揭示分子亚型和临床相关生物标志物。
我们进行了综合蛋白质基因组分析，以识别蛋白质组学亚型，评估BRAF V600突变的影响，并研究肿瘤微环境的分子谱和细胞组成。临床和组织病理学数据用于支持与组织形态、疾病进展和患者预后相关的研究结果。
我们的分析揭示了五种不同的蛋白质组学亚型，这些亚型整合了免疫和基质微环境成分，并与临床和组织病理学参数相关。我们证明，BRAF V600突变的黑色素瘤表现出生物学异质性，其中一种癌基因诱导的衰老样表型与生存率提高相关。这导致了一种基于死亡风险的分层方法，可能有助于制定更个性化的治疗策略。此外，肿瘤微环境组成与疾病进展和患者预后密切相关，突出了组织病理学结缔组织与肿瘤比例评估作为一种潜在决策工具的重要性。我们确定了一种与黑色素瘤相关的SAAV特征，与细胞外基质重塑有关，并且SAAV衍生的新抗原可作为抗肿瘤免疫反应的潜在靶点。
本研究提供了转移性黑色素瘤的全面分层，将蛋白质基因组学见解与组织病理学特征相结合。这些发现可能有助于制定量身定制的诊断和治疗策略，改善患者管理和预后。
