Combining gemcitabine and MSC delivering soluble TRAIL to target pancreatic adenocarcinoma and its stroma.
Gemcitabine
Deoxycytidine
/ analogs & derivatives
Humans
TNF-Related Apoptosis-Inducing Ligand
/ pharmacology
Pancreatic Neoplasms
/ pathology
Mesenchymal Stem Cells
/ metabolism
Animals
Cell Line, Tumor
Mice
Carcinoma, Pancreatic Ductal
/ pathology
Xenograft Model Antitumor Assays
Cancer-Associated Fibroblasts
/ metabolism
Adenocarcinoma
/ pathology
Journal
Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894
Informations de publication
Date de publication:
20 Aug 2024
20 Aug 2024
Historique:
received:
31
05
2023
revised:
13
05
2024
accepted:
22
07
2024
medline:
22
8
2024
pubmed:
22
8
2024
entrez:
21
8
2024
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 39168103
pii: S2666-3791(24)00406-3
doi: 10.1016/j.xcrm.2024.101685
pii:
doi:
Substances chimiques
Gemcitabine
0
Deoxycytidine
0W860991D6
TNF-Related Apoptosis-Inducing Ligand
0
TNFSF10 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
101685Informations de copyright
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests M. Dominici and G.G. hold patents in the field of cell and gene therapy. EIR Biotherapies srl holds patents related to the presented technologies. M. Dall’Ora and O.C. are employees of EVOTEC Modena Srl.