Combining gemcitabine and MSC delivering soluble TRAIL to target pancreatic adenocarcinoma and its stroma
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.
Authors
- Valentina Masciale (ORCID: https://orcid.org/0000-0003-1708-8785)
- Giulia Casari (ORCID: https://orcid.org/0009-0008-2881-3894)
- Elena Veronesi (ORCID: https://orcid.org/0000-0001-6262-1388)
- Federico Banchelli (ORCID: https://orcid.org/0000-0003-0499-2505)
- Fabrizio Di Benedetto (ORCID: https://orcid.org/0000-0002-6718-8760)
- Manuela Ferracin (ORCID: https://orcid.org/0000-0002-1595-6887)
- Jonathan Vinet (ORCID: https://orcid.org/0000-0001-9011-6207)
- F. Leporé (ORCID: https://orcid.org/0000-0003-4196-1775)
- Andrea Spallanzani (ORCID: https://orcid.org/0000-0001-6955-7139)
- Barbara Catellani
- Massimo Dominici (ORCID: https://orcid.org/0000-0002-4007-1503)
- Riccardo Cuoghi Costantini (ORCID: https://orcid.org/0000-0002-9116-5198)
- Angela d’Esposito
- Paolo Magistri (ORCID: https://orcid.org/0000-0001-8326-069X)
- Carlotta Spano
- Massimiliano Dall’Ora
- Olivia Candini (ORCID: https://orcid.org/0000-0002-5749-9100)
- Edwin M. Horwitz (ORCID: https://orcid.org/0000-0002-3751-4027)
- Tiziana Petrachi (ORCID: https://orcid.org/0000-0001-9399-9957)
- Moein Farshchian (ORCID: https://orcid.org/0000-0002-1228-048X)
- Aurora Melandri
- Albino Eccher (ORCID: https://orcid.org/0000-0002-9992-5550)
- Roberta Roncarati (ORCID: https://orcid.org/0000-0002-2371-3316)
- Giulia Grisendi (ORCID: https://orcid.org/0000-0002-0120-6129)
- Caterina Marra (ORCID: https://orcid.org/0000-0002-3511-8127)
- Chiara Chiavelli (ORCID: https://orcid.org/0000-0002-1551-7702)
- Luca Reggiani Bonetti (ORCID: https://orcid.org/0000-0002-9917-4080)
- Giliola Spattini
Institutions
- University of Modena and Reggio Emilia (IT)
- Marche Polytechnic University (IT)
- Emory University (US)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Istituto di Genetica Molecolare (IT)
- Ospedale di Mirano (IT)
- University of Bologna (IT)
- Evotec (United States) (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-08-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101685
- Citations
- 10
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 2.83
Funders
- European Commission
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro