Breaking the cycle: Targeting of NDRG1 to inhibit bi‐directional oncogenic cross‐talk between pancreatic cancer and stroma

Pancreatic cancer (PaCa) is characterized by dense stroma that hinders treatment efficacy, with pancreatic stellate cells (PSCs) being a major contributor to this stromal barrier and PaCa progression. Activated PSCs release hepatocyte growth factor (HGF) insulin-like (IGF-1) induce proliferation, metastasis resistance chemotherapy. We demonstrate for the first time suppressor, N-myc downstream regulated gene 1 (NDRG1), potent inhibitor of PaCa-PSC cross-talk, leading inhibition HGF IGF-1 signaling. NDRG1 also potently reduced key driver metastasis, namely GLI1, PSC-mediated cell migration. The novel clinically trialed anticancer agent, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which upregulates NDRG1, de-sensitized ligands secreted activated PSCs. DpC inhibited PaCa-mediated activation via sonic hedgehog (SHH) In vivo, markedly tumor more avidly than standard chemotherapy disease, gemcitabine. Uniquely, was selectively cytotoxic against cells, while “re-programming” an inactive state, decreasing collagen deposition desmoplasia. Thus, targeting can effectively break oncogenic cycle bi-directional cross-talk overcome desmoplasia improve therapeutic outcomes.