Gold Nanoparticle Reprograms Pancreatic Tumor Microenvironment and Inhibits Tumor Growth

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 Mukherjee

Research output: Contribution to journalArticle

54 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10636-10651
Number of pages16
JournalACS Nano
Volume10
Issue number12
DOIs
StatePublished - Dec 27 2016

Keywords

  • gold nanoparticles
  • pancreatic cancer
  • stellate cells
  • tumor microenvironment

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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  • Cite this

    Saha, S., Xiong, X., Chakraborty, P. K., Shameer, K., Arvizo, R. R., Kudgus, R. A., Dwivedi, S. K. D., Hossen, M. N., Gillies, E. M., Robertson, J. D., Dudley, J. T., Urrutia, R. A., Postier, R. G., Bhattacharya, R., & Mukherjee, P. (2016). Gold Nanoparticle Reprograms Pancreatic Tumor Microenvironment and Inhibits Tumor Growth. ACS Nano, 10(12), 10636-10651. https://doi.org/10.1021/acsnano.6b02231