Combined action of suicide gene exosomes from pancreatic
cancer-associated fibroblasts and from mesenchymal stem cells
as a pancreatic ductal adenocarcinoma treatment approach

J 2025

Combined action of suicide gene exosomes from pancreatic cancer-associated fibroblasts and from mesenchymal stem cells as a pancreatic ductal adenocarcinoma treatment approach

JAKUBECHOVÁ, Jana; Uršula ALTANEROVÁ; Michal ANDREZÁL; Dajana VÁŇOVÁ; Tatiana ŽELEZNÍKOVÁ et al.

Základní údaje

Originální název

Combined action of suicide gene exosomes from pancreatic cancer-associated fibroblasts and from mesenchymal stem cells as a pancreatic ductal adenocarcinoma treatment approach

Autoři

Vydání

Cancer Cell International, BIOMED CENTRAL LTD, 2025, 1475-2867

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.000 v roce 2024

Označené pro přenos do RIV

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

Gene-directed enzyme prodrug therapy; Mesenchymal stem cells; Pancreatic cancer-associated fibroblasts; Pancreatic cancer intracellular treatment; Suicide gene exosomes

Štítky

CF CRYO, CF PROT

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 10. 3. 2026 12:34, Mgr. Eva Dubská

Anotace

V originále

The pancreatic cancer-associated fibroblasts (pCAFs) are among the most active components of the pancreatic ductal adenocarcinoma (PDAC). The pCAFs being of mesenchymal stem/stromal cell origin, interact directly with tumor stromal elements, modulate tumor development, and are involved in the formation of pre-metastatic niches that result in unsatisfactory PDAC treatment outcomes. This study aimed to develop an innovative approach for the treatment of desmoplastic pancreatic carcinoma via intracellularly targeted exosomes derived from pCAFs and from mesenchymal stem cells (MSCs) transduced with the suicide gene - yeast cytosine deaminase::uracil phosphoribosyl transferase (yCD::UPRT).MethodspCAFs were isolated from four PDAC tumor specimens and MSCs from various tissues. Their transduction with yCD::UPRT gene produce homogenous gene transduced cell populations capable of secreting suicide gene exosomes. Both gene- transduced and naive cells and their exosomes underwent characterization by biophysical, biochemical, microscopic, and LC-MS/MS proteomic methods. Tumor cell-killing functionality was assessed using three pancreatic cancer cell lines. The killing efficacy of combined suicide gene exosomes of MSCs and pCAFs was measured in a mixture of pCAFs and MIA PaCa-2 cells as a simulated desmoplastic pancreatic tumor in vitro.ResultsMSCs and pCAFs suicide gene exosomes act as cancer cell-targeted drugs, effectively killing pancreatic carcinoma cells. Exosomes intracellular convert the non-toxic prodrug 5-fluorocytosine into cytotoxic 5-fluorouracil and its metabolites in a dose-dependent manner. In experiments simulating the desmoplastic microenvironment of PDAC, we have found that the suicide gene exosomes from both cells conjugated with prodrug effectively target and inhibit the growth of simulated PDAC.ConclusionExosomes containing the yCD::UPRT gene from pCAFs and MSCs function as "Trojan horse" therapies, efficiently and dose-dependently eliminating pancreatic cancer cells. PDAC environment-targeted yCD::UPRT-gene exosomes from MSCs and pCAFs show promise for a novel PDAC treatment.

Návaznosti

EH23_015/0008175, projekt VaV

Název: Inovace České infrastruktury pro integrativní strukturní biologii

90242, velká výzkumná infrastruktura

Název: CIISB III

90254, velká výzkumná infrastruktura

Název: e-INFRA CZ II

Citovat

JAKUBECHOVÁ, Jana; Uršula ALTANEROVÁ; Michal ANDREZÁL; Dajana VÁŇOVÁ; Tatiana ŽELEZNÍKOVÁ; Peter BARTEK; Marína CIHOVÁ; Božena SMOLKOVÁ; Verona BUOCIKOVÁ; Peter MAKOVICKÝ; Kristína JAKIČ; Monika BURÍKOVÁ; Mária URBANOVÁ; Veronika REPASKÁ; Benjamin ŠPÁNIK; Miroslav TOMÁŠ; Peter DUBOVAN; Georgína KOLNÍKOVÁ; Zbyněk ZDRÁHAL; Václav PUSTKA; David POTĚŠIL a Čestmír ALTANER. Combined action of suicide gene exosomes from pancreatic cancer-associated fibroblasts and from mesenchymal stem cells as a pancreatic ductal adenocarcinoma treatment approach. Cancer Cell International. BIOMED CENTRAL LTD, 2025, roč. 26, DEC 20 2025, s. "35", 18 s. ISSN 1475-2867. Dostupné z: https://doi.org/10.1186/s12935-025-04130-0.

@article{2553908,
   author = {Jakubechová, Jana and Altanerová, Uršula and Andrezál, Michal and Váňová, Dajana and Železníková, Tatiana and Bartek, Peter and Cihová, Marína and Smolková, Božena and Buociková, Verona and Makovický, Peter and Jakič, Kristína and Buríková, Monika and Urbanová, Mária and Repaská, Veronika and Špánik, Benjamin and Tomáš, Miroslav and Dubovan, Peter and Kolníková, Georgína and Zdráhal, Zbyněk and Pustka, Václav and Potěšil, David and Altaner, Čestmír},
   article_number = {DEC 20 2025},
   doi = {https://doi.org/10.1186/s12935-025-04130-0},
   keywords = {Gene-directed enzyme prodrug therapy; Mesenchymal stem cells; Pancreatic cancer-associated fibroblasts; Pancreatic cancer intracellular treatment; Suicide gene exosomes},
   language = {eng},
   issn = {1475-2867},
   journal = {Cancer Cell International},
   title = {Combined action of suicide gene exosomes from pancreatic cancer-associated fibroblasts and from mesenchymal stem cells as a pancreatic ductal adenocarcinoma treatment approach},
   url = {https://link.springer.com/article/10.1186/s12935-025-04130-0},
   volume = {26},
   year = {2025}
}

TY  - JOUR
ID  - 2553908
AU  - Jakubechová, Jana - Altanerová, Uršula - Andrezál, Michal - Váňová, Dajana - Železníková, Tatiana - Bartek, Peter - Cihová, Marína - Smolková, Božena - Buociková, Verona - Makovický, Peter - Jakič, Kristína - Buríková, Monika - Urbanová, Mária - Repaská, Veronika - Špánik, Benjamin - Tomáš, Miroslav - Dubovan, Peter - Kolníková, Georgína - Zdráhal, Zbyněk - Pustka, Václav - Potěšil, David - Altaner, Čestmír
PY  - 2025
TI  - Combined action of suicide gene exosomes from pancreatic cancer-associated fibroblasts and from mesenchymal stem cells as a pancreatic ductal adenocarcinoma treatment approach
JF  - Cancer Cell International
VL  - 26
IS  - DEC 20 2025
SP  - "35"
EP  - "35"
PB  - BIOMED CENTRAL LTD
SN  - 14752867
KW  - Gene-directed enzyme prodrug therapy
KW  - Mesenchymal stem cells
KW  - Pancreatic cancer-associated fibroblasts
KW  - Pancreatic cancer intracellular treatment
KW  - Suicide gene exosomes
UR  - https://link.springer.com/article/10.1186/s12935-025-04130-0
N2  - The pancreatic cancer-associated fibroblasts (pCAFs) are among the most active components of the pancreatic ductal adenocarcinoma (PDAC). The pCAFs being of mesenchymal stem/stromal cell origin, interact directly with tumor stromal elements, modulate tumor development, and are involved in the formation of pre-metastatic niches that result in unsatisfactory PDAC treatment outcomes. This study aimed to develop an innovative approach for the treatment of desmoplastic pancreatic carcinoma via intracellularly targeted exosomes derived from pCAFs and from mesenchymal stem cells (MSCs) transduced with the suicide gene - yeast cytosine deaminase::uracil phosphoribosyl transferase (yCD::UPRT).MethodspCAFs were isolated from four PDAC tumor specimens and MSCs from various tissues. Their transduction with yCD::UPRT gene produce homogenous gene transduced cell populations capable of secreting suicide gene exosomes. Both gene- transduced and naive cells and their exosomes underwent characterization by biophysical, biochemical, microscopic, and LC-MS/MS proteomic methods. Tumor cell-killing functionality was assessed using three pancreatic cancer cell lines. The killing efficacy of combined suicide gene exosomes of MSCs and pCAFs was measured in a mixture of pCAFs and MIA PaCa-2 cells as a simulated desmoplastic pancreatic tumor in vitro.ResultsMSCs and pCAFs suicide gene exosomes act as cancer cell-targeted drugs, effectively killing pancreatic carcinoma cells. Exosomes intracellular convert the non-toxic prodrug 5-fluorocytosine into cytotoxic 5-fluorouracil and its metabolites in a dose-dependent manner. In experiments simulating the desmoplastic microenvironment of PDAC, we have found that the suicide gene exosomes from both cells conjugated with prodrug effectively target and inhibit the growth of simulated PDAC.ConclusionExosomes containing the yCD::UPRT gene from pCAFs and MSCs function as "Trojan horse" therapies, efficiently and dose-dependently eliminating pancreatic cancer cells. PDAC environment-targeted yCD::UPRT-gene exosomes from MSCs and pCAFs show promise for a novel PDAC treatment.
ER  -

JAKUBECHOVÁ, Jana; Uršula ALTANEROVÁ; Michal ANDREZÁL; Dajana VÁŇOVÁ; Tatiana ŽELEZNÍKOVÁ; Peter BARTEK; Marína CIHOVÁ; Božena SMOLKOVÁ; Verona BUOCIKOVÁ; Peter MAKOVICKÝ; Kristína JAKIČ; Monika BURÍKOVÁ; Mária URBANOVÁ; Veronika REPASKÁ; Benjamin ŠPÁNIK; Miroslav TOMÁŠ; Peter DUBOVAN; Georgína KOLNÍKOVÁ; Zbyněk ZDRÁHAL; Václav PUSTKA; David POTĚŠIL a Čestmír ALTANER. Combined action of suicide gene exosomes from pancreatic cancer-associated fibroblasts and from mesenchymal stem cells as a pancreatic ductal adenocarcinoma treatment approach. \textit{Cancer Cell International}. BIOMED CENTRAL LTD, 2025, roč.~26, DEC 20 2025, s.~''35'', 18 s. ISSN~1475-2867. Dostupné z: https://doi.org/10.1186/s12935-025-04130-0.

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