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Gold Nanoparticle Reprograms Pancreatic Tumor Microenvironment and Inhibits Tumor Growth. ACS Nano 2016 12 27;10(12):10636-10651 PMID: 27758098

Pubmed ID

27758098

DOI

10.1021/acsnano.6b02231

Abstract

Altered tumor microenvironment (TME) arising from a bidirectional crosstalk between the pancreatic cancer cells (PCCs) and the pancreatic stellate cells (PSCs) is implicated in the dismal prognosis in pancreatic ductal adenocarcinoma (PDAC), yet effective strategies to disrupt the crosstalk is lacking. Here, we demonstrate that gold nanoparticles (AuNPs) inhibit proliferation and migration of both PCCs and PSCs by disrupting the bidirectional communication via alteration of the cell secretome. Analyzing the key proteins identified from a functional network of AuNP-altered secretome in PCCs and PSCs, we demonstrate that AuNPs impair secretions of major hub node proteins in both cell types and transform activated PSCs toward a lipid-rich quiescent phenotype. By reducing activation of PSCs, AuNPs inhibit matrix deposition, enhance angiogenesis, and inhibit tumor growth in an orthotopic co-implantation model in vivo. Auto- and heteroregulations of secretory growth factors/cytokines are disrupted by AuNPs resulting in reprogramming of the TME. By utilizing a kinase dead mutant of IRE1-α, we demonstrate that AuNPs alter the cellular secretome through the ER-stress-regulated IRE1-dependent decay pathway (RIDD) and identify endostatin and matrix metalloproteinase 9 as putative RIDD targets. Thus, AuNPs could potentially be utilized as a tool to effectively interrogate bidirectional communications in the tumor microenvironment, reprogram it, and inhibit tumor growth by its therapeutic function.

Author List

Saha S, Xiong X, Chakraborty PK, Shameer K, Arvizo RR, Kudgus RA, Dwivedi SK, Hossen MN, Gillies EM, Robertson JD, Dudley JT, Urrutia RA, Postier RG, Bhattacharya R, Mukherjee P

Author

Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-85007559438   26 Citations

MESH terms used to index this publication - Major topics in bold

Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Gold
Humans
Metal Nanoparticles
Pancreatic Neoplasms
Pancreatic Stellate Cells
Tumor Microenvironment
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad