Abstract B081: Synergistic paracrine action of Vitamin D and mesenchymal stem cell secretome in targeting pancreatic cancer stem cells

Abstract

Abstract The knowledge of immunomodulatory and reparative properties of Mesenchymal Stem cells (MSCs) are rapidly advancing and could be best suited as a therapeutic option for inflammatory or adverse immunological conditions such as cancer. In the last decade, Mesenchymal stem cells have attracted significant attention because of their accessibility, tumor-oriented homing capacity and the transplantation feasibility. Until date, MSC-based therapy for pancreatic cancer has not been demonstrated. As per the current understanding of the potentials of MSCs in regenerative medicine, we hypothesized their inhibitory influence on pancreatic cancer cells. For experimentation purposes, we have used human Wharton’s jelly derived MSCs (hWJ-MSCs) and pancreatic cell line models. Our findings show that secretion of soluble biologically active factors from hWJ-MSCs (secretome) had a greater impact on induction of anergy and apoptosis of pancreatic tumor cells. The mechanistic approach directed to influence the tumor microenvironment appear to be two pronged: one, via modulation of tumor glycoproteins (MUC-1 and EpCAM) and second, via GSK3β/Stat3/HIF1-α axis. Treatment with calcitriol, an analogue of Vitamin D known to regulate cell cycle, cell differentiation ca also reduce side effects of chemo-drugs, one of the mainstay of therapy in pancreatic cancer. Yet, the potential mechanism to exert anti-cancer effect remains underexplored. We attempted to elicit the involvement of VitD in one of the crucial stem-cell related embryonic pathway, the Sonic Hedgehog (SHH) pathway. Our data showed enhanced apoptosis of calcitirol treated-pCSCs cells when treated with salinomycin (SHH inhibitor). Further combinatorial treatment with secretome + VitD decreased copy numbers of transcription factors C-myc, SMO, PTCH1, PTCH2, and hypoxia-induced factor (HIF1-α) demonstrating the potential mechanism of action. In conclusion, our experimental evidence postulates a potential mechanism by which VitD-analogue regulate sHH-mTOR axis and in combination with mesenchymal stem cell secretome can affect the proliferation and migratory (oncogenic) capabilities of pancreatic cancer stem cells. So, what next? Do we have the evidence to suggest secretome as a novel cell-free therapeutic candidate!! Citation Format: Sangeeta Choudhury, Neha Chopra, Kriti Jain, Poonam Yadav, Surinder P. Singh, Yashika Charla. Synergistic paracrine action of Vitamin D and mesenchymal stem cell secretome in targeting pancreatic cancer stem cells [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B081.