胰导管腺癌（PDAC）是一种具有不良生存率的侵袭性癌症。为了探索K-Ras原癌基因的未知功能，我们激活了间充质干细胞（MSCs）中的K-Ras，并研究了MSC条件培养基（CM）对PDAC的影响。K-Ras的过表达提高了MSCs中的PI3K信号传导，而K-Ras/PI3K活化的MSC来源CM能够减少肿瘤细胞的增殖和迁移，以及体外新鲜分离的人类PDAC组织的生长。CM的抗肿瘤能力与常用PDAC化疗药物吉西他滨的作用具有叠加效应。在小鼠模型中，系统给予CM抑制了PDAC在肺部的定植。MSC CM富含杂睛蛋白（MSN），它通过与CD44相互作用发挥细胞外抗肿瘤蛋白的作用。PKA活化的外周血单个核细胞也能产生具有抑制肿瘤作用的CM。总体而言，本研究证明通过激活K-Ras和PI3K，可以通过工程化MSC CM来作为一种抑制肿瘤的药物选择，而MSN-CD44调控轴部分是其潜在治疗PDAC的非常规选项。© 2023. Springer Nature Limited.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival. To explore an uncharted function of K-Ras proto-oncogene, K-Ras was activated in mesenchymal stem cells (MSCs) and the effects of MSC conditioned medium (CM) on PDAC were examined. Overexpression of K-Ras elevated PI3K signaling in MSCs, and K-Ras/PI3K-activated MSC-derived CM reduced the proliferation and migration of tumor cells, as well as the growth of ex vivo freshly isolated human PDAC cultures. CM's anti-tumor capability was additive with Gemcitabine, a commonly used chemotherapeutic drug in the treatment of PDAC. The systemic administration of CM in a mouse model suppressed the colonization of PDAC in the lung. MSC CM was enriched with Moesin (MSN), which acted as an extracellular tumor-suppressing protein by interacting with CD44. Tumor-suppressive CM was also generated by PKA-activated peripheral blood mononuclear cells. Collectively, this study demonstrated that MSC CM can be engineered to act as a tumor-suppressive agent by activating K-Ras and PI3K, and the MSN-CD44 regulatory axis is in part responsible for this potential unconventional option in the treatment of PDAC.© 2023. Springer Nature Limited.