PO.TB03.06 · 肿瘤生物学
足底皮肤中的位点特异性微环境程序赋予肢端黑色素瘤更高的转移能力
A site-specific microenvironmental program in plantar skin confers heightened metastatic capacity to acral melanomas
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肢端黑色素瘤是一种侵袭性黑色素瘤亚型，倾向于转移且临床预后不良，然而目前尚无专门针对该人群获FDA批准的疗法。有限的临床-基因组数据和缺乏原位临床前模型阻碍了研究进展。在此，我们整合了来自29例转移性肢端黑色素瘤患者的基因组分析和纵向临床注释——同时对照一个455例皮肤黑色素瘤患者队列——揭示了肢端疾病中增强的转移能力。我们进一步表明，足底皮肤微环境通过升高的基质硬度培育出一种人类肢端黑色素瘤的促转移细胞状态，并鉴定出一个基质硬度诱导的FAK-SRC-YAP脆弱性，作为对抗远处转移的可治疗性可操作轴。这项工作建立了首批转移性肢端黑色素瘤原位模型，揭示了远处器官转移的可干预驱动因素，为量身定制的治疗策略提供了新途径。
查看英文原文 English abstract
Acral melanoma is an aggressive melanoma subtype with a predilection for metastasis and poor clinical outcomes, yet no FDA-approved therapies are tailored specifically for this population. Progress has been hindered by limited clinico-genomic data and a lack of orthotopic preclinical models. Here, we integrate genomic profiling and longitudinal clinical annotations from 29 patients with metastatic acral melanoma-alongside a comparison cohort of 455 patients with cutaneous melanoma-revealing an enhanced metastatic capacity in acral disease. We further show that the plantar skin microenvironment fosters a human acral melanoma, pro-metastatic cell state through elevated matrix stiffness, and identify a matrix stiffness-induced FAK-SRC-YAP vulnerability as a therapeutically actionable axis to combat distant metastasis. This work establishes the first series of orthotopic models of metastatic acral melanoma and uncovers tractable drivers of distant organ metastasis, offering new avenues for tailored therapeutic strategies.
利益披露 Disclosure
M. E. Portuallo, None..
T. Aprati, None..
L. An, None..
K. Yu, None.