Placental mesenchymal stem cells: A promising platform for advancing gene therapy in pancreatic ductal adenocarcinoma

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F25%3A00143966" target="_blank" >RIV/00216224:14740/25:00143966 - isvavai.cz</a>

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S0753332225006225?getft_integrator=scopus&pes=vor&utm_source=scopus" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0753332225006225?getft_integrator=scopus&pes=vor&utm_source=scopus</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.biopha.2025.118428" target="_blank" >10.1016/j.biopha.2025.118428</a>

Result language

angličtina

Original language name

Placental mesenchymal stem cells: A promising platform for advancing gene therapy in pancreatic ductal adenocarcinoma

Original language description

The extreme lethality and limited treatment options for pancreatic ductal adenocarcinoma (PDAC) underscore the urgent need for innovative therapeutic strategies. This study presents the first preclinical investigation of a cell-free gene-directed enzyme prodrug therapy (GDEPT) based on conditioned medium (CM) from placenta-derived mesenchymal stem cells (PlacMSCs) engineered to express the yeast cytosine deaminase::uracil phosphoribosyltransferase (yCD::UPRT) fusion enzyme. The CM was concentrated tenfold (cCM) and characterized by proteomics, transmission electron microscopy, and Western blotting, confirming extracellular vesicle (EV) enrichment and UPRT expression. Therapeutic efficacy was evaluated in coculture models comprising PDAC cell lines (BxPC-3, MIA PaCa-2, SU.86.86), patient-derived xenograft organoids (PDXOs), and cancer-associated fibroblasts (PCAFs). Immunocytochemistry and Western blot analyses revealed a predominant myofibroblastic CAF phenotype, characterized by strong alpha-smooth muscle actin (αSMA) expression and low interleukin-6 levels. Treatment with yCD::UPRT-PlacMSC-cCM in the presence of 5-fluorocytosine (5-FC) enabled efficient enzymatic conversion to 5-fluorouracil (5-FU), yielding 10 μg/mL from an initial 100 μg/mL of 5-FC. This resulted in robust, dose-dependent cytotoxicity (50 % to 80 % reduction in viability) across monocultures and stromal-rich cocultures, effectively overcoming PCAF-mediated drug resistance. Therapeutic response was governed primarily by tumor cell characteristics rather than PCAF heterogeneity. In PDXOs derived from two early-stage (IA, IIB) primary tumors and one metastatic lesion, 100 μL of yCD::UPRT-PlacMSC-cCM induced cytotoxicity comparable to 1 μg/mL of 5-FU, while 25 μL was insufficient to significantly reduce viability. Collectively, these findings demonstrate that yCD::UPRT-PlacMSC-cCM delivers potent, stromal-bypassing cytotoxicity in PDAC models and represents a promising cell-free therapeutic approach for this treatment-refractory cancer.

Czech name

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Czech description

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Type

J_SC - Article in a specialist periodical, which is included in the SCOPUS database

CEP classification

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OECD FORD branch

30204 - Oncology

Project

—

Continuities

—

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Biomedicine & Pharmacotherapy

ISSN

0753-3322

e-ISSN

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Volume of the periodical

190

Issue of the periodical within the volume

118428

Country of publishing house

AL - ALBANIA

Number of pages

14

Pages from-to

1-14

UT code for WoS article

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EID of the result in the Scopus database

2-s2.0-105012371677