de la Rosa Inés, Sisó Pol, Ríos Christopher, Gracia Judith, Cuevas Dolors, Maiques Oscar, Eritja Núria, Soria Xavier, Angel-Baldó Joan, Gatius Sonia, Sanchez-Moral Lidia, Sarrias Maria-Rosa, Matias-Guiu Xavier, Martí Rosa M, Macià Anna
Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain.
Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain.
Int J Mol Sci. 2025 Apr 25;26(9):4097. doi: 10.3390/ijms26094097.
Acral lentiginous melanoma (ALM) is a rare melanoma subtype primarily located in acral regions. However, ALMs exhibit a distinctive genetic profile characterized by a high number of copy number variations (CNVs) and limited point mutations. Late diagnosis and restricted therapeutic efficacy contribute to its poor prognosis. The secretome within the tumor microenvironment (TME) influences immune modulation and plays a vital role in melanoma progression. We aim to analyze the role of ALM secretome and CNVs profile with prognosis in primary ALM patients. Here, we demonstrated that high CNV burden (CNVsHigh) was associated with worse clinicopathological characteristics and poor prognosis. Furthermore, our study also revealed that conditioned media (CM) of CNVsHigh genetic profile ALM cell line was associated with pro-tumoral, pro-angiogenic, and immunosuppressive secretome profiles. In addition, CM of CNVsHigh cell lines in vitro promotes macrophage polarization to immunosuppressive phenotype. Moreover, we observed an increased presence of immunosuppressive tumor-associated macrophages (TAMs) at the invasive front (IF) of CNVsHigh ALM biopsies. This research reveals the adverse prognostic impact of CNVsHigh in ALM patients, establishing a novel link with a pro-tumor secretome, offering potential biomarkers for prognosis and personalized treatment to enhanced disease monitoring in ALM patients.
肢端雀斑样痣黑色素瘤（ALM）是一种罕见的黑色素瘤亚型，主要位于肢端部位。然而，ALM表现出独特的基因特征，其特点是拷贝数变异（CNV）数量多且点突变有限。诊断延迟和治疗效果受限导致其预后不良。肿瘤微环境（TME）中的分泌组影响免疫调节，在黑色素瘤进展中起关键作用。我们旨在分析原发性ALM患者中ALM分泌组和CNV谱与预后的关系。在此，我们证明高CNV负担（CNVsHigh）与更差的临床病理特征和不良预后相关。此外，我们的研究还表明，CNVsHigh基因谱ALM细胞系的条件培养基（CM）与促肿瘤、促血管生成和免疫抑制分泌组谱相关。此外，体外CNVsHigh细胞系的CM促进巨噬细胞极化为免疫抑制表型。此外，我们在CNVsHigh ALM活检的浸润前沿（IF）观察到免疫抑制性肿瘤相关巨噬细胞（TAM）的存在增加。这项研究揭示了CNVsHigh对ALM患者的不良预后影响，建立了与促肿瘤分泌组的新联系，为预后和个性化治疗提供了潜在的生物标志物，以加强对ALM患者的疾病监测。
