Yin Hanlin, Chen Qiangda, Gao Shanshan, Shoucair Sami, Xie Yuqi, Habib Joseph R, He Taochen, Gan Wei, Wang Juan, Zhang Lei, Xu Huaxiang, Shi Chenye, He Junyi, Wang Wenquan, Jin Yun, Goggins Michael G, Liu Liang, Lou Wenhui, Wu Wenchuan, Yu Jun, Pu Ning
Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Adv Sci (Weinh). 2025 Apr;12(14):e2417724. doi: 10.1002/advs.202417724. Epub 2025 Feb 18.
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, necessitating approaches to improve prognosis. As the mediator of allergic process, mast cells have been found in various cancers and are associated with survival. However, the biological behaviors of tumor-associated mast cells (TAMCs) remain unclear. Herein, an excessive infiltration of TAMCs in PDAC is demonstrated, which apparently associated with poor survival in PDAC patients. PDAC cells are found to recruit CXCR2 MCs into TME, and then inhibited MCs ferroptosis, and maintained their proliferation. Concomitantly, the tumor-derived exosome miR-188-5p activated the PTEN/AKT/GSK3β signaling, further stabilized transcriptional factor ERG by inhibiting its ubiquitin degradation, and finally enhanced the transcription of cxcl10 within TAMCs. In reverse, TAMCs-derived CXCL10 reversely promoted tumor epithelial-mesenchymal transition and induced immunosuppressive tumor microenvironment by recruiting CXCR3 Tregs. Sodium cromoglycate (SCG) is a membrane stabilizer for MCs and confirmed as an effective and widely used agent to block TAMCs-derived CXCL10 and further sensitize the therapeutic efficacy of anti-PD-1 antibody plus gemcitabine for PDAC. These findings illuminate a critical and innovative crosstalk between TAMCs and PDAC cells that promote PDAC progression, and SCG sensitizes PDAC to the current immuno-chemotherapy, which reveals its potential to be a valuable adjuvant for PDAC patients.
胰腺导管腺癌（PDAC）是一种毁灭性疾病，需要采取措施改善预后。作为过敏反应过程的介质，肥大细胞已在多种癌症中被发现，并与生存率相关。然而，肿瘤相关肥大细胞（TAMCs）的生物学行为仍不清楚。在此，研究表明TAMCs在PDAC中过度浸润，这显然与PDAC患者的不良生存相关。研究发现，PDAC细胞将CXCR2⁺肥大细胞招募到肿瘤微环境（TME）中，然后抑制肥大细胞的铁死亡，并维持其增殖。同时，肿瘤来源的外泌体miR-188-5p激活PTEN/AKT/GSK3β信号通路，通过抑制转录因子ERG的泛素降解进一步使其稳定，最终增强TAMCs内cxcl10的转录。相反，TAMCs来源的CXCL10通过招募CXCR3⁺调节性T细胞（Tregs）反向促进肿瘤上皮-间质转化并诱导免疫抑制性肿瘤微环境。色甘酸钠（SCG）是一种肥大细胞膜稳定剂，被证实是一种有效且广泛使用的药物，可阻断TAMCs来源的CXCL10，并进一步增强抗PD-1抗体联合吉西他滨对PDAC的治疗效果。这些发现揭示了TAMCs与PDAC细胞之间促进PDAC进展的关键且创新的相互作用，并且SCG使PDAC对当前的免疫化疗敏感，这揭示了其作为PDAC患者有价值辅助药物的潜力。
