Convergent roles of GDF-15 in mechanotransduction, vascular disorganization, and immune suppression in melanoma

• 成果类型: Article
• 署名作者: Chen, Yu-Chi; Bollu, Vishnu Sravan; Kheirabadi, Sina; LaPenna, Kyle; Berg, Arthur; He, Pingnian; Schell, Todd D.; Sheikhi, Amir; Tabdanov, Erdem D.; Robertson, Gavin P.
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2602594123
• 发表日期: 2026-09-01
• 页码: e2602594123
• 关键词: growth differentiation factor-15; ECM rigidity; GelMA; acral melanoma; cutaneous melanoma; MACROPHAGE INHIBITORY CYTOKINE-1; DIFFERENTIATION FACTOR 15; MALIGNANT-MELANOMA; GROWTH; cancer; permeability; gdf15; cytoskeleton

摘要

Melanoma, particularly in its advanced forms, remains one of the most lethal skin cancers, with limited effective treatments for both common cutaneous subtypes and rarer variants such as acral melanoma. The effects of the extracellular matrix (ECM) and other cancer-cell extrinsic processes on melanoma development remain underexplored. This study identifies growth differentiation factor-15 (GDF-15) as a mechanosensing-regulated driver of melanoma pathogenesis across melanoma types. GDF-15 is shown here to be mechanically induced by ECM rigidity and compressive forces occurring during metastatic progression, leading to significantly elevated levels in both cutaneous and acral melanoma cells. In this study, ECM rigidity was recapitulated using cell-adhesive gelatin methacryloyl (GelMA) hydrogel microparticles (microgels) with tunable stiffness, providing a biomimetic platform to investigate how mechanical cues in the tumor microenvironment regulate GDF-15 expression in melanoma. A previously unrecognized synergy between GDF-15 and inflammatory factors commonly present in tumors was identified and found to promote a disorganized, hyperpermeable vasculature, thereby facilitating tumor nutrient access and impeding effective immune cell infiltration. GDF-15 knockdown reduced the intratumoral hemorrhage phenotype, indicating a causal role. GDF-15 also functions by directly suppressing natural killer (NK) cell-mediated cytotoxicity, revealing a second cooperating mechanism of immune evasion. These effects position GDF-15 as a key node linking mechanical stress, co-operation with inflammatory factors, abnormal vascular development, and immune dysfunction, thereby converging on pathways and processes relevant to melanoma progression and treatment.