Department of Metabolism and Physiology, Moffitt Cancer Center, Tampa, FL, USA.
Department of Biostatistics and Bioinformatics at the Moffitt Cancer Center, Tampa, FL, USA.
Cell Rep Med. 2024 Jun 18;5(6):101606. doi: 10.1016/j.xcrm.2024.101606. Epub 2024 Jun 11.
Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. Here, we characterize the tumor microenvironment of LMD and patient-matched extra-cranial metastases using spatial transcriptomics in a small number of clinical specimens (nine tissues from two patients) with extensive in vitro and in vivo validation. The spatial landscape of melanoma LMD is characterized by a lack of immune infiltration and instead exhibits a higher level of stromal involvement. The tumor-stroma interactions at the leptomeninges activate tumor-promoting signaling, mediated through upregulation of SERPINA3. The meningeal stroma is required for melanoma cells to survive in the cerebrospinal fluid (CSF) and promotes MAPK inhibitor resistance. Knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in tumor cell death and re-sensitization to MAPK-targeting therapy. Our data provide a spatial atlas of melanoma LMD, identify the tumor-promoting role of meningeal stroma, and demonstrate a mechanism for overcoming microenvironment-mediated drug resistance in LMD.
脑膜疾病（LMD）仍然是晚期黑色素瘤患者迅速致命的并发症。在这里，我们使用空间转录组学在少量临床标本（两名患者的九种组织）中对 LMD 和患者匹配的颅外转移进行了特征描述，这些标本经过了广泛的体外和体内验证。黑色素瘤 LMD 的空间景观的特征是缺乏免疫浸润，而是表现出更高水平的基质参与。软脑膜处的肿瘤-基质相互作用激活了肿瘤促进信号，这是通过 SERPINA3 的上调介导的。脑膜基质对于黑色素瘤细胞在脑脊液（CSF）中存活是必需的，并促进 MAPK 抑制剂耐药性。敲低 SERPINA3 或抑制下游 IGR1R/PI3K/AKT 轴可导致肿瘤细胞死亡，并重新对 MAPK 靶向治疗敏感。我们的数据提供了黑色素瘤 LMD 的空间图谱，确定了脑膜基质的肿瘤促进作用，并展示了克服 LMD 中微环境介导的药物耐药性的机制。
