title: Gold Nanoparticle Reprograms Pancreatic Tumor Microenvironment and Inhibits Tumor Growth.
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.
authors.forename: Sounik
authors.initials: S
authors.lastname: Saha
authors.forename: Xunhao
authors.initials: X
authors.lastname: Xiong
authors.forename: Prabir K
authors.initials: PK
authors.lastname: Chakraborty
authors.affiliation: Institute of Next Generation Healthcare, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System , New York, New York 10029, United States.
authors.forename: Khader
authors.initials: K
authors.lastname: Shameer
authors.forename: Rochelle R
authors.initials: RR
authors.lastname: Arvizo
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Kudgus
authors.forename: Shailendra Kumar Dhar
authors.initials: SK
authors.lastname: Dwivedi
authors.forename: Md Nazir
authors.initials: MN
authors.lastname: Hossen
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Gillies
authors.affiliation: Department of Chemistry and University of Missouri Research Reactor, University of Missouri , Columbia, Missouri 65211, United States.
authors.forename: J David
authors.initials: JD
authors.lastname: Robertson
authors.affiliation: Institute of Next Generation Healthcare, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System , New York, New York 10029, United States.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.forename: Raul A
authors.initials: RA
authors.lastname: Urrutia
authors.forename: Russell G
authors.initials: RG
authors.lastname: Postier
authors.forename: Resham
authors.initials: R
authors.lastname: Bhattacharya
authors.forename: Priyabrata
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006046:Gold; D006801:Humans; D053768:Metal Nanoparticles; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000628:therapy*; D058954:Pancreatic Stellate Cells; D059016:Tumor Microenvironment
chemical_list: D006046:Gold
keywords: gold nanoparticles; pancreatic cancer; stellate cells; tumor microenvironment