Targeting Wnt/tenascin C-mediated cross talk between pancreatic cancer cells and stellate cells via activation of the metastasis suppressor NDRG1

Bekesho Geleta; Faten S Tout; Syer Choon Lim; Sumit Sahni; Patric J Jansson; Minoti V Apte; Des R Richardson; Žaklina Kovačević

doi:10.1016/j.jbc.2022.101608

Targeting Wnt/tenascin C-mediated cross talk between pancreatic cancer cells and stellate cells via activation of the metastasis suppressor NDRG1

J Biol Chem. 2022 Mar;298(3):101608. doi: 10.1016/j.jbc.2022.101608. Epub 2022 Jan 20.

Authors

Bekesho Geleta¹, Faten S Tout², Syer Choon Lim¹, Sumit Sahni³, Patric J Jansson⁴, Minoti V Apte⁵, Des R Richardson⁶, Žaklina Kovačević⁷

Affiliations

¹ Cancer Metastasis and Tumor Microenvironment Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia.
² Cancer Metastasis and Tumor Microenvironment Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Department of Medical Laboratory Science, Faculty of Allied Health Sciences, The Hashemite University, Zarqa, Jordan.
³ Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
⁴ Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia; Cancer Drug Resistance & Stem Cell Program, Faculty of Medicine and Health, School of Medical Science, University of Sydney, Sydney, New South Wales, Australia.
⁵ Pancreatic Research Group, South Western Sydney Clinical School, UNSW Sydney, Sydney, New South Wales, Australia; Pancreatic Research Group, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia.
⁶ Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁷ Cancer Metastasis and Tumor Microenvironment Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia. Electronic address: zaklina.kovacevic@sydney.edu.au.

Abstract

A major barrier to successful pancreatic cancer (PC) treatment is the surrounding stroma, which secretes growth factors/cytokines that promote PC progression. Wnt and tenascin C (TnC) are key ligands secreted by stromal pancreatic stellate cells (PSCs) that then act on PC cells in a paracrine manner to activate the oncogenic β-catenin and YAP/TAZ signaling pathways. Therefore, therapies targeting oncogenic Wnt/TnC cross talk between PC cells and PSCs constitute a promising new therapeutic approach for PC treatment. The metastasis suppressor N-myc downstream-regulated gene-1 (NDRG1) inhibits tumor progression and metastasis in numerous cancers, including PC. We demonstrate herein that targeting NDRG1 using the clinically trialed anticancer agent di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) inhibited Wnt/TnC-mediated interactions between PC cells and the surrounding PSCs. Mechanistically, NDRG1 and DpC markedly inhibit secretion of Wnt3a and TnC by PSCs, while also attenuating Wnt/β-catenin and YAP/TAZ activation and downstream signaling in PC cells. This antioncogenic activity was mediated by direct inhibition of β-catenin and YAP/TAZ nuclear localization and by increasing the Wnt inhibitor, DKK1. Expression of NDRG1 also inhibited transforming growth factor (TGF)-β secretion by PC cells, a key mechanism by which PC cells activate PSCs. Using an in vivo orthotopic PC mouse model, we show DpC downregulated β-catenin, TnC, and YAP/TAZ, while potently increasing NDRG1 expression in PC tumors. We conclude that NDRG1 and DpC inhibit Wnt/TnC-mediated interactions between PC cells and PSCs. These results further illuminate the antioncogenic mechanism of NDRG1 and the potential of targeting this metastasis suppressor to overcome the oncogenic effects of the PC-PSC interaction.

Keywords: NDRG1; TnC; Wnt; pancreatic cancer; tumor microenvironment.

MeSH terms

Animals
Cell Communication*
Cell Cycle Proteins* / genetics
Cell Cycle Proteins* / metabolism
Cell Line, Tumor
Intracellular Signaling Peptides and Proteins* / genetics
Intracellular Signaling Peptides and Proteins* / metabolism
Mice
Neoplasm Metastasis
Pancreatic Neoplasms* / metabolism
Pancreatic Neoplasms* / pathology
Pancreatic Stellate Cells* / metabolism
Pancreatic Stellate Cells* / pathology
Tenascin* / genetics
Tenascin* / metabolism
beta Catenin* / genetics
beta Catenin* / metabolism

Substances

CTNNB1 protein, mouse
Cell Cycle Proteins
Intracellular Signaling Peptides and Proteins
N-myc downstream-regulated gene 1 protein
Tenascin
Tnc protein, mouse
beta Catenin