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Gold Nanoparticle Reprograms Pancreatic Tumor Microenvironment and Inhibits Tumor Growth
journal contribution
posted on 2016-10-18, 13:52 authored by Sounik Saha, Xunhao Xiong, Prabir
K. Chakraborty, Khader Shameer, Rochelle R. Arvizo, Rachel A. Kudgus, Shailendra Kumar
Dhar Dwivedi, Md. Nazir Hossen, Elizabeth M. Gillies, J. David Robertson, Joel
T. Dudley, Raul A. Urrutia, Russell G. Postier, Resham Bhattacharya, Priyabrata MukherjeeAltered 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.
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pancreatic ductal adenocarcinomaER-stress-regulated IRE 1-dependent decay pathwaypancreatic cancer cellsPCCRIDDsecretomegold Nanoparticle Reprograms Pancreatic Tumor Microenvironmentpancreatic stellate cellsbidirectionalAuNPPSCtumor growthPDACTMEorthotopic co-implantation modelInhibits Tumor Growth Altered tumor microenvironmenthub node proteinsmatrix metalloproteinase 9
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