Li Xinyuan, Li Kai, Li Mengmeng, Lin Xiaoyu, Mei Yu, Huang Xuemei, Yang Huanjie
School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
Front Oncol. 2022 Feb 9;12:844648. doi: 10.3389/fonc.2022.844648. eCollection 2022.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Gemcitabine is the most commonly used chemotherapy for the treatment of PDAC, but the development of drug resistance still remains challenging. Recently, exosomes have emerged as important mediators for intercellular communication. Exosomes affect recipient cells' behavior through the engulfed cargos, however the specific cargos responsible for gemcitabine resistance in PDAC are poorly understood. Here, we reported that exosomes could transfer gemcitabine resistance a metalloproteinase 14 (MMP14)-dependent mechanism. MMP14 was identified as a major differentially secreted protein from the gemcitabine-resistant PDAC cells by comparative secretome. It was packaged into the exosomes and transmitted from the chemoresistant cells to the sensitive ones. The exosome-transferred MMP14 could enhance drug resistance and promotes the sphere-formation and migration abilities of the recipient sensitive PDAC cells. Mechanically, exosome-transferred MMP14 promotes the stability of CD44, the cancer stem cell marker in the recipient cells. Our results indicate that MMP14 is a key player for exosome-mediated transfer of gemcitabine resistance, thus targeting MMP14 in exosomes may represent a novel strategy to limit gemcitabine resistance in PDAC.
胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一。吉西他滨是治疗PDAC最常用的化疗药物，但耐药性的产生仍然具有挑战性。最近，外泌体已成为细胞间通讯的重要介质。外泌体通过所携带的货物影响受体细胞的行为，然而，导致PDAC对吉西他滨耐药的具体货物尚不清楚。在此，我们报道外泌体可通过一种依赖金属蛋白酶14（MMP14）的机制传递吉西他滨耐药性。通过比较分泌组学，MMP14被鉴定为吉西他滨耐药的PDAC细胞中一种主要的差异分泌蛋白。它被包装到外泌体中，并从化疗耐药细胞传递到敏感细胞。外泌体传递的MMP14可增强耐药性，并促进受体敏感PDAC细胞的成球和迁移能力。从机制上讲，外泌体传递的MMP14促进了受体细胞中癌症干细胞标志物CD44的稳定性。我们的结果表明，MMP14是外泌体介导的吉西他滨耐药性转移的关键因素，因此靶向外泌体中的MMP14可能代表一种限制PDAC中吉西他滨耐药性的新策略。
