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.

Using Gold Nanoparticles To Disrupt the Tumor Microenvironment: An Emerging Therapeutic Strategy

“…For example, AuNPs (20 nm diameter) were found to reduce proliferation in PSCs and PCCs significantly but not in normal human pancreatic ductal epithelial cells or nonmalignant NIH3T3 fibroblasts. 6 These observations are in good agreement with previous findings that AuNPs do not modulate the proliferation of normal ovarian epithelial cells 10,11 and do not induce systemic toxicity following 3–4 weeks of repeated injections. 10,11 This reduction in proliferation was determined to result, at least in part, from suppression of mitogen-activated protein kinase (MAPK) signaling, which mediates growth-factor-induced proliferation.…”

“…), the current research has identified exciting novel properties of AuNPs as stand-alone cancer therapeutics for PDAC. 6 These results are particularly interesting because AuNPs were demonstrated to exert this therapeutic behavior specifically within populations of cancer cells but not nonmalignant cells. For example, AuNPs (20 nm diameter) were found to reduce proliferation in PSCs and PCCs significantly but not in normal human pancreatic ductal epithelial cells or nonmalignant NIH3T3 fibroblasts.…”

“…In this issue of ACS Nano , Mukherjee and colleagues report that bare gold nanoparticles (AuNPs) can modulate the tumor microenvironment to inhibit the proliferation and migration of both tumor and stromal cells in pancreatic ductal adenocarcinoma (PDAC) (Figure 1). 6 This work suggests that AuNPs exhibit innate properties that can be exploited to interrogate crosstalk mechanisms within the tumor microenvironment and disrupt these communications to produce a therapeutic outcome.…”

“…Using AuNPs as a platform to investigate and to manipulate signaling between PSCs and PCCs, Mukherjee and colleagues report several interesting findings regarding the use of AuNPs as both stand-alone therapeutics and tools for crosstalk analysis. 6 …”

“…Further, AuNP-treated PSCs return to a more quiescent phenotype, indicated by decreased ECM protein production, reduced α -SMA expression, and restored lipid metabolism. 6 …”