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

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.

• Authors: Bekesho Geleta, Kyung Chan Park, Patric J Jansson, Sumit Sahni, Sanaz Maleki, Zhihong Xu, Takashi Murakami, Marina Pajic, Minoti V Apte, Des R Richardson, Zaklina Kovacevic
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 35 Issue 2 Pg. e21347 (02 2021) ISSN: 1530-6860 [Electronic] United States
• PMID: 33484481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Federation of American Societies for Experimental Biology.

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• GLI1 protein, human
• Hedgehog Proteins
• IGF1 protein, human
• Intracellular Signaling Peptides and Proteins
• N-myc downstream-regulated gene 1 protein
• Pyridines
• SHH protein, human
• Thiosemicarbazones
• Zinc Finger Protein GLI1
• di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone
• Hepatocyte Growth Factor
• Insulin-Like Growth Factor I

Topics

• Adenocarcinoma (metabolism, pathology)
• Animals
• Antineoplastic Agents (toxicity)
• Cell Cycle Proteins (metabolism)
• Cell Line
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Female
• Hedgehog Proteins (metabolism)
• Hepatocyte Growth Factor (metabolism)
• Humans
• Insulin-Like Growth Factor I (metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Pancreatic Neoplasms (metabolism, pathology)
• Pyridines (toxicity)
• Stromal Cells (drug effects, metabolism)
• Thiosemicarbazones (toxicity)
• Zinc Finger Protein GLI1 (metabolism)