胰腺癌仍然是最致命的恶性疾病之一。以吉西他滨为基础的化疗仍然是一线全身治疗方法之一，但大多数患者会出现化疗耐药。最近，积累的证据证明了肿瘤微环境在促进化疗耐药中的作用。在肿瘤微环境中，胰腺星状细胞（PSC）是主要细胞成分之一，细胞外囊泡（EV）是细胞间通讯的常见介质。在这项研究中，我们发现SP1转录的miR-31-5p不仅靶向胰腺癌细胞中的LATS2，而且还通过EV转移调节PSC中的Hippo通路。因此，PSC 合成并分泌富含半胱氨酸的酸性蛋白 (SPARC)，该蛋白优先在基质细胞中表达，刺激胰腺癌细胞中的细胞外信号调节激酶 (ERK) 信号传导。因此，由于 miR-31-5p 调节的内在 Hippo 通路和外部 SPARC 诱导的 ERK 信号传导，胰腺癌细胞的存活率和化疗耐药性得到改善。在小鼠模型中，胰腺癌细胞中 miR-31-5p 的过度表达促进了共注射异种移植物的化疗耐药性。在组织微阵列中，miR-31-5p 表达较高的胰腺癌患者的总生存期较短。因此，miR-31-5p 通过 EV 调节肿瘤微环境中多种细胞类型的 Hippo 通路，最终有助于胰腺癌细胞的化疗耐药性。© 2024 作者。 《Journal of Extracellular Vesicles》由 Wiley periodicals LLC 代表国际细胞外囊泡学会出版。

Pancreatic cancer remains one of the most lethal malignant diseases. Gemcitabine-based chemotherapy is still one of the first-line systemic treatments, but chemoresistance occurs in the majority of patients. Recently, accumulated evidence has demonstrated the role of the tumour microenvironment in promoting chemoresistance. In the tumour microenvironment, pancreatic stellate cells (PSCs) are among the main cellular components, and extracellular vesicles (EVs) are common mediators of cell‒cell communication. In this study, we showed that SP1-transcribed miR-31-5p not only targeted LATS2 in pancreatic cancer cells but also regulated the Hippo pathway in PSCs through EV transfer. Consequently, PSCs synthesized and secreted protein acidic and rich in cysteins (SPARC), which was preferentially expressed in stromal cells, stimulating Extracellular Signal regulated kinase (ERK) signalling in pancreatic cancer cells. Therefore, pancreatic cancer cell survival and chemoresistance were improved due to both the intrinsic Hippo pathway regulated by miR-31-5p and external SPARC-induced ERK signalling. In mouse models, miR-31-5p overexpression in pancreatic cancer cells promoted the chemoresistance of coinjected xenografts. In a tissue microarray, pancreatic cancer patients with higher miR-31-5p expression had shorter overall survival. Therefore, miR-31-5p regulates the Hippo pathway in multiple cell types within the tumour microenvironment via EVs, ultimately contributing to the chemoresistance of pancreatic cancer cells.© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.