Combining gemcitabine and MSC delivering soluble TRAIL to target pancreatic adenocarcinoma and its stroma.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-08-20 DOI:10.1016/j.xcrm.2024.101685

Giulia Grisendi, Massimiliano Dall'Ora, Giulia Casari, Giliola Spattini, Moein Farshchian, Aurora Melandri, Valentina Masicale, Fabio Lepore, Federico Banchelli, Riccardo Cuoghi Costantini, Angela D'Esposito, Chiara Chiavelli, Carlotta Spano, Andrea Spallanzani, Tiziana Petrachi, Elena Veronesi, Manuela Ferracin, Roberta Roncarati, Jonathan Vinet, Paolo Magistri, Barbara Catellani, Olivia Candini, Caterina Marra, Albino Eccher, Luca Reggiani Bonetti, Edwin M Horwtiz, Fabrizio Di Benedetto, Massimo Dominici

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Abstract

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.

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将吉西他滨和输送可溶性 TRAIL 的间充质干细胞结合起来，靶向胰腺癌及其基质。

胰腺导管腺癌（PDAC）对疗法的反应仍然不佳，部分原因是其癌症相关成纤维细胞（CAFs）。在这里，我们研究了吉西他滨（GEM）等已知化疗药物与分泌促凋亡可溶性（s）TRAIL（sTRAIL MSCs）的基因修饰人间质基质/干细胞（MSCs）之间的联合疗法对 PDAC 细胞和 CAFs 的协同作用。在二维和三维模型中，该组合明显影响了 PDAC 的存活。在正位异种移植模型中，GEM 和 sTRAIL 间充质干细胞可诱导肿瘤结构粉碎，减少 CK7 和 CK8/18 阳性癌细胞，并抑制脾脏转移。此外，我们还观察到细胞间充质干细胞对原发性人类 CAFs 具有细胞毒性作用，同时还改变了它们的转录组，减少了相关的脱钙现象。总之，我们证明了结合 GEM 和 sTRAIL 间充质干细胞针对 PDAC 的肿瘤和基质部分具有良好的治疗效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.