Tuesday, April 1, 2025
4/1/2025
Protein-nanoparticle interaction to study multicellular crosstalk within ovarian tumor microenviroment - The tumor microenvironment (TME) plays a critical role in poor prognosis in many cancers including ovarian and pancreatic cancer. However, key perpetrators executing the multicellular crosstalk within the TME still remains elusive. Exploiting protein-nanoparticle interaction to investigate multicellular crosstalk within the TME will provide new avenues for biological characterization of the disease. More than a decade ago we serendipitously discovered that gold nanoparticles (GNPs) possess anti- angiogenic property. In our initial efforts we deciphered the molecular mechanisms of this property, showing that of various sized GNPs, those of 20 nm diameter most effectively inhibited activity of several pro-angiogenic heparin-binding growth factors (HB-GFs) by altering protein conformation. Later we coined the term “self- therapeutic nanoparticle” to define the intrinsic activity of GNPs and showed that, by reversing epithelial- mesenchymal transition and abrogating MAPK-signaling through downregulation of HB-GFs, GNPs inhibited tumor growth, metastasis, and drug resistance in epithelial ovarian cancer (EOC), without any toxicity. Using ovarian patient-derived xenograft (PDX) and multicellular human xenograft models (MCX, generated by co-implanting equal numbers of CC, CAF and EC) we showed that GNPs disrupted CC-CAF-EC crosstalk to inhibit tumor growth. However, key molecular machineries executing the multicellular crosstalk still remain elusive. Importantly, we further showed that GNP treatment reduced Insulin Growth Factor Binding Protein 2 (IGFBP2) expression in tumor tissues and serum from MCX and PDX animals, indicating IGFBP2 may be a key player driving the crosstalk. We will test our hypotheses in the following aims: Aim 1: Deciphering domains of IGFBP2 responsible for multicellular crosstalk by nanoparticles. Aim 2: Silencing IGFBP2 to study multicellular crosstalk in vitro and vivo. The current proposal represents a unique example of how nanotechnology could be exploited as a tool to unravel molecular intricacies operating within the TME and an effective way to confirm the role of the key perpetrator contributing to tumor growth by siRNA delivery-based gene silencing approach.
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