Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Sci Transl Med. 2024 Apr 3;16(741):eadj5705. doi: 10.1126/scitranslmed.adj5705.
Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 (TSPAN8) myofibroblastic CAF (myCAF) subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts of patients with breast cancer (BC). TSPAN8 myCAFs potentiate the stemness of the surrounding BC cells through secretion of senescence-associated secretory phenotype (SASP)-related factors IL-6 and IL-8 to counteract chemotherapy. NAD-dependent protein deacetylase sirtuin 6 (SIRT6) reduction was responsible for the senescence-like phenotype and tumor-promoting role of TSPAN8 myCAFs. Mechanistically, TSPAN8 promoted the phosphorylation of ubiquitin E3 ligase retinoblastoma binding protein 6 (RBBP6) at Ser by recruiting MAPK11, thereby inducing SIRT6 protein destruction. In turn, SIRT6 down-regulation up-regulated and , which caused TSPAN8 myCAFs to secrete aspartate and proline, and therefore proved a nutritional niche to support BC outgrowth. By demonstrating that TSPAN8SIRT6 myCAFs were tightly associated with unfavorable disease outcomes, we proposed that the combined regimen of anti-TSPAN8 antibody and SIRT6 activator MDL-800 is a promising approach to overcome chemoresistance. These findings highlight that senescence contributes to CAF heterogeneity and chemoresistance and suggest that targeting TSPAN8 myCAFs is a promising approach to circumvent chemoresistance.
癌症相关成纤维细胞（CAFs）是肿瘤微环境中丰富的基质细胞，可促进癌症的进展和复发。然而，化学抗性背后的 CAF 的异质性和调节作用在很大程度上仍不清楚。在这里，我们使用高维流式细胞术分析进行了单细胞分析，鉴定了一种独特的衰老样四跨膜蛋白 8（TSPAN8）肌成纤维 CAF（myCAF）亚群，该亚群与多个乳腺癌（BC）患者队列中的治疗耐药性和不良预后相关。TSPAN8myCAFs 通过分泌与衰老相关的分泌表型（SASP）相关因子 IL-6 和 IL-8 来增强周围 BC 细胞的干性，从而抵消化疗。NAD 依赖性蛋白去乙酰化酶 Sirtuin 6（SIRT6）的减少负责 TSPAN8myCAFs 的衰老样表型和促肿瘤作用。在机制上，TSPAN8 通过募集 MAPK11 促进泛素 E3 连接酶视网膜母细胞瘤结合蛋白 6（RBBP6）在丝氨酸上的磷酸化，从而诱导 SIRT6 蛋白降解。反过来，SIRT6 的下调上调了和，这导致 TSPAN8myCAFs 分泌天冬氨酸和脯氨酸，从而为 BC 的生长提供了营养小生境。通过证明 TSPAN8SIRT6myCAFs 与不良疾病结局密切相关，我们提出联合使用抗 TSPAN8 抗体和 SIRT6 激活剂 MDL-800 的方案是克服化疗耐药性的一种很有前途的方法。这些发现强调了衰老对 CAF 异质性和化疗耐药性的贡献，并表明靶向 TSPAN8myCAFs 是克服化疗耐药性的一种很有前途的方法。
