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Updated: Jun 15, 2025
Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies
Published on: June 20, 2015
Combining gemcitabine and MSC delivering soluble TRAIL to target pancreatic adenocarcinoma and its stroma
Giulia Grisendi1, Massimiliano Dall'Ora2, Giulia Casari3
1Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia (UNIMORE), Modena, Italy.
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.
Insights
This study shows combining gemcitabine chemotherapy with modified stem cells secreting sTRAIL effectively targets pancreatic cancer cells and their supportive fibroblasts. This approach reduces tumor growth and metastasis in preclinical models.
Area of Science:
- Oncology
- Cancer Biology
- Stem Cell Therapy
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits poor therapeutic responses, partly attributed to cancer-associated fibroblasts (CAFs).
- Targeting both cancer cells and the tumor microenvironment is crucial for effective PDAC treatment.
Purpose of the Study:
- To investigate the synergistic effect of gemcitabine (GEM) combined with gene-modified mesenchymal stromal/stem cells (MSCs) secreting soluble TRAIL (sTRAIL MSCs) on PDAC and CAFs.
- To evaluate this combination therapy in preclinical models of pancreatic cancer.
Main Methods:
- Utilized 2D and 3D cell culture models and orthotopic xenograft models in mice.
- Administered gemcitabine (GEM) and sTRAIL-secreting MSCs (sTRAIL MSCs) as a combination therapy.
- Assessed tumor cell survival, tumor architecture, metastasis, and CAF characteristics.
Main Results:
- The combination therapy significantly reduced PDAC cell survival in vitro and in vivo.
- Observed tumor architecture disruption, decreased cancer cell markers (CK7, CK8/18), and reduced spleen metastasis in xenograft models.
- Demonstrated cytotoxic effects on CAFs, altered their transcriptome, and reduced desmoplasia.
Conclusions:
- Combining GEM with sTRAIL MSCs shows a promising therapeutic strategy for PDAC.
- This approach effectively targets both the tumoral and stromal compartments of pancreatic cancer.
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