SOLUBLE TRAIL-ARMED HUMAN AD-MSC AS NOVEL CELL THERAPY APPROACH FOR PANCREATIC DUCTAL ADENOCARCINOMA

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive adult tumors and its prognosis is still poor since the number of deaths almost equal the number of new cases. New therapeutic approaches are therefore urgently needed. In our model human adipose mesenchy.mal stromallstem cells (ADMSC) have been armed with a novel soluble TRAIL variant that is constantly released by modified progenitors (sTRAIL AD-MSC). The wild type TRAIL form is known to act as a trimer stabilized by a zinc-binding site. In this srudy, by gene engineering, we allow AD-MSC to secrete a trimeric zincindependent soluble TRAIL variant. The molecule has been then challenged in vitro and in vivo, either using sTRAIL AD-MSC supernatant or injecting sTRAIL AD-MSC cells in a PDAC xenotransplant rnodel, We demonstrated that sTRAIL was stable at 37°C far at least 24 hours and was able to induce apoptosis in the PDAC lines BxPC-3 and MIA PaCa-2 and, more interestingly, against primary PDAC cells. Moreover, sTRAIL released by AD-MSC was able to significantly counteract tumor growth with a reduction of the cytokeratin-7 positive cells and by an anti-angiogenic effect. In parallel, a retrospective study on PDAC specimens form patients (n = 19) has been conducted in order to investigate TRAIL DR4, DR5 and OPG receptor expression in "real" PDAC tissue and generate insights on the possible clinical translation of our approach. Our results suggest that MSC can be vehicles for novel TRAIL variants opening novel opportunities for PDAC treatrnent by multiple mechanisms.