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. [Display omitted] •MSC sTRAIL and GEM combo kills TRAIL-sensitive and resistant PDAC lines•GEM sensitizes CAF to MSC sTRAIL apoptosis impacting on their transcriptome•The combo reduces desmoplastic reaction in a 3D tumor avatar model•The combo induces tumor shredding and reduction of metastases in murine models By 2D and 3D in vitro models combined with 2 orthotopic xenografts, Grisendi et al. demonstrate that chemotherapy with gemcitabine in combo with an MSC-delivered TRAIL efficiently targets both pancreatic cancer cells and their fibroblasts (CAFs), inducing apoptosis, modifying CAF transcriptome, reducing tumor-driven desmoplastic reaction, and, ultimately, abrogating metastases.