Background and Aims: Pancreatic cancer (PaCa) is characterized by a dense stroma surrounding the tumor cells composed of mainly pancreatic stellate cells (PSCs), which are activated by Sonic hedgehog (SHH) produced by PaCa cells. In turn, activated PSCs release cytokines and growth factors, such as hepatocyte growth factor (HGF), insulin-like growth factor (IGF-1), and interleukin 6 (IL-6), that stimulate proliferation and metastatic ability of PaCa cells. N-myc downstream regulated gene 1 (NDRG1) is a metastasis suppressor and potent inhibitor of numerous oncogenic signaling pathways in PaCa cells. We hypothesized that targeting NDRG1 using the novel clinically trialed anticancer agent, di (2-pyridyl) ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), may interrupt the oncogenic cross-talk between PSCs and PaCa cells. Methods: We examined the effects of NDRG1 and DpC on: (1) HGF and IGF-1 receptor activation and down-stream signaling in PaCa cells; (2) PaCa-mediated production of SHH; and (3) activation of PSCs and their ability to produce HGF, IGF-1, and IL-6. To assess the tumor–stromal interaction, we used PSC and AsPC-1 conditioned media, 3D coculture spheroids, and an orthotopic in vivo model that incorporates both PaCa cells and PSC cells. Results: We demonstrate that DpC potently inhibits the activation of HGF and IGF-1 pathways in PaCa cells, with this effect being dependent on NDRG1. DpC also inhibited SHH signaling and PSC activation, leading to reduced production of HGF, IGF, and IL-6 by these stromal cells. In vivo, DpC markedly reduced PaCa tumor growth and metastasis, being more effective than gemcitabine. Conclusion: Targeting NDRG1 with DpC can interrupt the bidirectional cross-talk between PaCa and PSCs, breaking the oncogenic cycle that promotes desmoplasia. This presents a unique and innovative opportunity to overcome the desmoplasia of PaCa and constitutes a novel approach to overcoming PaCa progression and metastasis.