Breaking the cycle: Targeting of NDRG1 to inhibit bi‐directional oncogenic cross‐talk between pancreatic cancer and stroma
- 23 January 2021
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 35 (2), e21347
- https://doi.org/10.1096/fj.202002279r
Abstract
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) and insulin-like growth factor (IGF-1) that induce PaCa proliferation, metastasis and resistance to chemotherapy. We demonstrate for the first time that the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), is a potent inhibitor of the PaCa-PSC cross-talk, leading to inhibition of HGF and IGF-1 signaling. NDRG1 also potently reduced the key driver of PaCa metastasis, namely GLI1, leading to reduced PSC-mediated cell migration. The novel clinically trialed anticancer agent, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which upregulates NDRG1, potently de-sensitized PaCa cells to ligands secreted by activated PSCs. DpC and NDRG1 also inhibited the PaCa-mediated activation of PSCs via inhibition of sonic hedgehog (SHH) signaling. In vivo, DpC markedly reduced PaCa tumor growth and metastasis more avidly than the standard chemotherapy for this disease, gemcitabine. Uniquely, DpC was selectively cytotoxic against PaCa cells, while "re-programming" PSCs to an inactive state, decreasing collagen deposition and desmoplasia. Thus, targeting NDRG1 can effectively break the oncogenic cycle of PaCa-PSC bi-directional cross-talk to overcome PaCa desmoplasia and improve therapeutic outcomes.Keywords
Funding Information
- Cure Cancer Australia Foundation (#APP1125107)
This publication has 60 references indexed in Scilit:
- Targeting the HGF/c-MET pathway: stromal remodelling in pancreatic cancerOncotarget, 2017
- Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under HypoxiaPLOS ONE, 2016
- The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling PathwaysOnline Journal of Public Health Informatics, 2016
- Pancreatic stellate cells and pancreas cancer: Current perspectives and future strategiesEuropean Journal of Cancer, 2014
- Sonic Hedgehog Paracrine Signaling Activates Stromal Cells to Promote Perineural Invasion in Pancreatic CancerClinical Cancer Research, 2014
- The role of the hepatocyte growth factor/c-MET pathway in pancreatic stellate cell–endothelial cell interactions: antiangiogenic implications in pancreatic cancerCarcinogenesis: Integrative Cancer Research, 2014
- α-Smooth Muscle Actin Expressing Stroma Promotes an Aggressive Tumor Biology in Pancreatic Ductal AdenocarcinomaPancreas, 2010
- Stromal biology and therapy in pancreatic cancerGut, 2010
- Tumor–stromal interactions with direct cell contacts enhance proliferation of human pancreatic carcinoma cellsCancer Science, 2009
- Sonic Hedgehog Promotes Desmoplasia in Pancreatic CancerClinical Cancer Research, 2008