br TGF signaling plays an important role
TGF-β signaling plays an important role in cancer-stromal crosstalk and is an important driver of fibroblast activation [10,23,26,27]. P-SMAD2 expression is an indicator of active canonical TGF-β signaling and this occurs in both cancer and stromal CAY10444 . We observed that an increasing number of stromal cells exhibit p-SMAD2 expression in metastatic vs. primary sites (Fig. 3) implicating activation of TGF-β signaling in OC metastasis. Supporting the proposed importance of TGF-β in metastases, we have demonstrated that inhibition of TGF-β signaling delays tumor growth and suppresses ascites development in OC xenograft models . Collectively these observations demonstrate the potential of TGF-β signaling targeting as a therapeutic strategy in
An important strength of our study is that we begin to compare gene expression between primary and metastatic sites and this highlights the significant heterogeneity across tumor sites. Understanding this hetero-geneity within individual patients is important as it will be a limitation of triage or therapy based biopsy strategy. Our study has some impor-tant limitations. The study was performed on 45 patient samples from only 15 patients and assessing subtle difference in expression between sites is somewhat subjective. A larger study will be required to validate these findings and to investigate the clinical significance of patterns of
Fig. 3. P-SMAD2 expression in metastatic vs. primary MES subtype of HGSOC.
expression. We demonstrated that all tested gene signatures mainly arise from stroma rather than cancer cells but the specific impact of these proteins in OC behavior is not known. Further functional study of these genes is required.
In conclusion, this is the first study to clearly show that the origins of MES subtype gene signatures derive substantially from stroma rather than cancer cells in OC. This observation supports the value of stroma targeting in treatment of MES subtype HGSOC patients.
Supplementary data to this article can be found online at https://doi.
Conflicts of interest
None of the authors has any conflicts of interest to declare.
This research was supported by the Mayo Clinic Specialized Program in Research Excellence (SPORE) grant CA136393 and the Minnesota Ovarian Cancer Alliance (MOCA).
CRediT authorship contribution statement
Qing Zhang: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Re-sources, Software, Validation, Visualization, Writing - original draft, Writing - review & editing. Chen Wang: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Validation, Visualization. William A. Cliby: Conceptualization, Formal analysis, Funding acquisi-tion, Investigation, Project administration, Resources, Supervision, Visual-ization, Writing - original draft, Writing - review & editing.
 Z. Liu, et al., Suboptimal cytoreduction in ovarian carcinoma is associated with mo-lecular pathways characteristic of increased stromal activation, Gynecol. Oncol. 139 (3) (2015) 394–400.
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Cancer-selective nanoparticles for combinatorial siRNA delivery to primary T human GBM in vitro and in vivo
Kristen L. Kozielskia,b, Alejandro Ruiz-Vallsc, Stephany Y. Tzenga, Hugo Guerrero-Cázaresc,d, Yuan Ruia, Yuxin Lic, Hannah J. Vaughana, Marissa Gionet-Gonzalesa, Casey Vantuccia, Jayoung Kima, Paula Schiapparellic,d, Rawan Al-Kharbooshc,d, Alfredo Quiñones-Hinojosac,d,∗∗, Jordan J. Greena,c,e,∗
a Department of Biomedical Engineering, Translational Tissue Engineering Center, And Institute for NanoBioTechnology, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA b Max Planck Institute for Intelligent Systems, Heisenbergstr. 3, Stuttgart, 70569, Germany
c Departments of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
d Department of Neurosurgery, Mayo Clinic, Jacksonville, FL, 32224, USA
e Department of Materials Science and Engineering, Department of Chemical and Biomolecular Engineering, Department of Ophthalmology, The Sidney Kimmel Comprehensive Cancer, And the Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA
Novel treatments for glioblastoma (GBM) are urgently needed, particularly those which can simultaneously target GBM cells’ ability to grow and migrate. Herein, we describe a synthetic, bioreducible, biodegradable polymer that can package and deliver hundreds of siRNA molecules into a single nanoparticle, facilitating combination therapy against multiple GBM-promoting targets. We demonstrate that siRNA delivery with these polymeric nanoparticles is cancer-selective, thereby avoiding potential side eﬀects in healthy cells. We show that we can deliver siRNAs targeting several anti-GBM genes (Robo1, YAP1, NKCC1, EGFR, and survivin) simulta-neously and within the same nanoparticles. Robo1 (roundabout homolog 1) siRNA delivery by biodegradable particles was found to trigger GBM cell death, as did non-viral delivery of NKCC1, EGFR, and survivin siRNA. Most importantly, combining several anti-GBM siRNAs into a nanoparticle formulation leads to high GBM cell death, reduces GBM migration in vitro, and reduces tumor burden over time following intratumoral adminis-tration. We show that certain genes, like survivin and EGFR, are important for GBM survival, while NKCC1, is more crucial for cancer cell migration. This represents a powerful platform technology with the potential to serve as a multimodal therapeutic for cancer.