Combining Gemcitabine and MSC Delivering Soluble TRAIL to Target Pancreatic Adenocarcinoma and Their Stroma

Pancreatic ductal adenocarcinoma (PDAC) notoriously has a poor response to available therapies, partly due to its fibrotic stroma and its cancer-associated fibroblasts (CAF). We have been focusing on the development of therapeutic strategies able to target both malignant cells and CAF. Here, we investigated the potential synergistic impact of a novel combinatory approach between the chemotherapy agent gemcitabine (GEM) and an anticancer gene therapy based on human adipose mesenchymal stromal/stem cells (MSC) secreting the pro-apoptotic multimeric soluble (s)TRAIL (sTRAIL MSC) on both PDAC tumor and CAF. The efficacy of the combo GEM+sTRAIL approach was tested in vitro against PDAC cell lines and on primary PDAC CAF alone in both 2D and 3D culture systems. In addition, two orthotopic PDAC xenogenic murine models were developed and, to further validate the strategy, a 3D PDAC avatar model was generated loading PDAC cells together with primary CAF. The in vitro combinatory approach significantly impacted on PDAC survival both in 2D and 3D models. GEM+sTRAIL MSC also dramatically induced the shredding of tumor architecture with a significant reduction of CK7 and CK8/18 positive tumor cells and the abrogation of spleen metastases. The therapeutic relevance of this combined treatment was further confirmed in the 3D avatar model where data also indicated a cytotoxicity of the combinatory approach on primary human CAF along with the alteration of their transcriptome and the reduction of desmoplastic reaction. We here demonstrated the promising therapeutic profile of combining an unconventional gene therapy delivered by MSC with a standard chemotherapy agent to target both tumoral and stromal compartments in PDAC.