胰腺导管腺癌 (PDAC) 对治疗的反应仍然较差，部分原因是其癌症相关成纤维细胞 (CAF)。在这里，我们研究了已知化疗药物（例如吉西他滨 (GEM)）与分泌促凋亡可溶性 (s)TRAIL (sTRAIL MSCs) 的基因修饰人间充质基质/干细胞 (MSC) 之间的组合方法的协同影响。 ）在 PDAC 细胞和 CAF 上。该组合对 2D 和 3D 模型中 PDAC 的存活有显着影响。在原位异种移植模型中，GEM 和 sTRAIL MSC 诱导肿瘤结构粉碎，减少 CK7 和 CK8/18 阳性癌细胞并消除脾转移。还观察到对原代人 CAF 的细胞毒性作用以及其转录组的改变和相关结缔组织形成的减少。总的来说，我们展示了结合 GEM 和 sTRAIL MSC 来靶向 PDAC 中的肿瘤和基质区室的有前景的治疗方案。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Pancreatic ductal adenocarcinoma (PDAC) still has a poor response to therapies, partly due to their cancer-associated fibroblasts (CAFs). Here, we investigate the synergistic impact of a combinatory approach between a known chemotherapy agent, such as gemcitabine (GEM), and gene-modified human mesenchymal stromal/stem cells (MSCs) secreting the pro-apoptotic soluble (s)TRAIL (sTRAIL MSCs) on both PDAC cells and CAFs. The combo significantly impacts on PDAC survival in 2D and 3D models. In orthotopic xenograft models, GEM and sTRAIL MSCs induce tumor architecture shredding with a reduction of CK7- and CK8/18-positive cancer cells and the abrogation of spleen metastases. A cytotoxic effect on primary human CAFs is also observed along with an alteration of their transcriptome and a reduction of the related desmoplasia. Collectively, we demonstrate a promising therapeutic profile of combining GEM and sTRAIL MSCs to target both tumoral and stromal compartments in PDAC.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.