TY - JOUR
T1 - Gold Nanoparticle Reprograms Pancreatic Tumor Microenvironment and Inhibits Tumor Growth
AU - Saha, Sounik
AU - Xiong, Xunhao
AU - Chakraborty, Prabir K.
AU - Shameer, Khader
AU - Arvizo, Rochelle R.
AU - Kudgus, Rachel A.
AU - Dwivedi, Shailendra Kumar Dhar
AU - Hossen, Md Nazir
AU - Gillies, Elizabeth M.
AU - Robertson, J. David
AU - Dudley, Joel T.
AU - Urrutia, Raul A.
AU - Postier, Russell G.
AU - Bhattacharya, Resham
AU - Mukherjee, Priyabrata
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/12/27
Y1 - 2016/12/27
N2 - 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.
AB - 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.
KW - gold nanoparticles
KW - pancreatic cancer
KW - stellate cells
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85007559438&partnerID=8YFLogxK
U2 - 10.1021/acsnano.6b02231
DO - 10.1021/acsnano.6b02231
M3 - Article
C2 - 27758098
AN - SCOPUS:85007559438
SN - 1936-0851
VL - 10
SP - 10636
EP - 10651
JO - ACS Nano
JF - ACS Nano
IS - 12
ER -