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1. Investigating the Interactions of Glioma Stem Cells in the Perivascular Niche at Single‐Cell Resolution using a Microfluidic Tumor Microenvironment Model

   https://doi.org/10.1002/advs.202201436  

   Adjei‐Sowah, Emmanuela_A; O'Connor, Samantha_A; Veldhuizen, Jaimeson; Lo_Cascio, Costanza; Plaisier, Christopher; Mehta, Shwetal; Nikkhah, Mehdi (May 2022, Advanced Science)

   Abstract The perivascular niche (PVN) is a glioblastoma tumor microenvironment (TME) that serves as a safe haven for glioma stem cells (GSCs), and acts as a reservoir that inevitably leads to tumor recurrence. Understanding cellular interactions in the PVN that drive GSC treatment resistance and stemness is crucial to develop lasting therapies for glioblastoma. The limitations of in vivo models and in vitro assays have led to critical knowledge gaps regarding the influence of various cell types in the PVN on GSCs behavior. This study developed an organotypic triculture microfluidic model as a means to recapitulate the PVN and study its impact on GSCs. This triculture platform, comprised of endothelial cells (ECs), astrocytes, and GSCs, is used to investigate GSC invasion, proliferation and stemness. Both ECs and astrocytes significantly increased invasiveness of GSCs. This study futher identified 15 ligand‐receptor pairs using single‐cell RNAseq with putative chemotactic mechanisms of GSCs, where the receptor is up‐regulated in GSCs and the diffusible ligand is expressed in either astrocytes or ECs. Notably, the ligand–receptor pair SAA1‐FPR1 is demonstrated to be involved in chemotactic invasion of GSCs toward PVN. The novel triculture platform presented herein can be used for therapeutic development and discovery of molecular mechanisms driving GSC biology. 

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2. Advancing Targeted Drug Delivery in Glioblastoma Multiforme Through Biomimetic Nanomedicine Using 3D Tumor‐On‐a‐Chip Model

   https://doi.org/10.1002/adhm.202502454  

   Manoharan, Twinkle_Jina_Minette; Wang, Ting‐Yun; Mantri, Shivani; Alarnous, Hanan; Mehta, Shwetal; Wang, Kuei‐Chun; Nikkhah, Mehdi (September 2025, Advanced Healthcare Materials)

   Abstract The prognosis of glioblastoma multiforme (GBM) remains dismal, despite standard treatment regimens. A key challenge in treating GBM is the persistence of glioma stem cells (GSCs) within the perivascular niche (PVN) – a protective tumor microenvironment (TME) that is often associated with inadequate drug penetration. Current preclinical models do not capture complexity of the human TME, particularly the vasculature and niche‐specific interactions that drive GBM progression. To overcome these limitations, an innovative 3Dex‐vivotumor‐on‐a‐chip (TOC) platform is engineered to accurately replicate the structural and functional characteristics of the PVN. Using this platform, this study demonstrates that monocyte membrane‐coated nanoparticles (MoNP) effectively target the abnormal tumor microvasculature, offering a promising approach to enhance drug delivery to these hard‐to‐reach GSCs. The results show that the therapeutic agent verteporfin, when delivered via MoNP, significantly inhibited GSC growth and invasiveness, while the free‐form drug showed minimal efficacy. Comprehensive transcriptomic profiling and cytokine analysis validated the TOC model's ability to reflect authentic GSC responses and confirmed that MoNP‐mediated verteporfin delivery effectively modulates key tumor‐related signaling pathways. This integrated TOC‐MoNP platform represents a clinically relevant tool that bridges the gap between traditional preclinical models and human disease, providing new opportunities for developing more effective GBM therapies. 

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3. Characterization of Ablation Thresholds for 3D-Cultured Patient-Derived Glioma Stem Cells in Response to High-Frequency Irreversible Electroporation

   https://doi.org/10.34133/2019/8081315  

   Ivey, J. W.; Wasson, E. M.; Alinezhadbalalami, N.; Kanitkar, A.; Debinski, W.; Sheng, Z.; Davalos, R. V.; Verbridge, S. S. (April 2019, Research)

   High-frequency irreversible electroporation (H-FIRE) is a technique that uses pulsed electric fields that have been shown to ablate malignant cells. In order to evaluate the clinical potential of H-FIRE to treat glioblastoma (GBM), a primary brain tumor, we have studied the effects of high-frequency waveforms on therapy-resistant glioma stem-like cell (GSC) populations. We demonstrate that patient-derived GSCs are more susceptible to H-FIRE damage than primary normal astrocytes. This selectivity presents an opportunity for a degree of malignant cell targeting as bulk tumor cells and tumor stem cells are seen to exhibit similar lethal electric field thresholds, significantly lower than that of healthy astrocytes. However, neural stem cell (NSC) populations also exhibit a similar sensitivity to these pulses. This observation may suggest that different considerations be taken when applying these therapies in younger versus older patients, where the importance of preserving NSC populations may impose different restrictions on use. We also demonstrate variability in threshold among the three patient-derived GSC lines studied, suggesting the need for personalized cell-specific characterization in the development of potential clinical procedures. Future work may provide further useful insights regarding this patient-dependent variability observed that could inform targeted and personalized treatment. 

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4. Single B Cell Gene Co-Expression Networks Implicated in Prognosis, Proliferation, and Therapeutic Responses in Non-Small Cell Lung Cancer Bulk Tumors

   https://doi.org/10.3390/cancers14133123  

   Ye, Qing; Guo, Nancy Lan (July 2022, Cancers)

   In NSCLC, there is a pressing need for immunotherapy predictive biomarkers. The processes underlying B-cell dysfunction, as well as their prognostic importance in NSCLC, are unknown. Tumor-specific B-cell gene co-expression networks were constructed by comparing the Boolean implication modeling of single-cell RNA sequencing of NSCLC tumor B cells and normal B cells. Proliferation genes were selected from the networks using in vitro CRISPR-Cas9/RNA interfering (RNAi) screening data in more than 92 human NSCLC epithelial cell lines. The prognostic and predictive evaluation was performed using public NSCLC transcriptome and proteome profiles. A B cell proliferation and prognostic gene co-expression network was present only in normal lung B cells and missing in NSCLC tumor B cells. A nine-gene signature was identified from this B cell network that provided accurate prognostic stratification using bulk NSCLC tumor transcriptome (n = 1313) and proteome profiles (n = 103). Multiple genes (HLA-DRA, HLA-DRB1, OAS1, and CD74) differentially expressed in NSCLC B cells, peripheral blood lymphocytes, and tumor T cells had concordant prognostic indications at the mRNA and protein expression levels. The selected genes were associated with drug sensitivity/resistance to 10 commonly used NSCLC therapeutic regimens. Lestaurtinib was discovered as a potential repositioning drug for treating NSCLC. 

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5. Liposome Formulation for Tumor-Targeted Drug Delivery Using Radiation Therapy

   https://doi.org/10.3390/ijms231911662  

   Stolarz, Amanda J.; Chhetri, Bijay P.; Borrelli, Michael J.; Jenkins, Samir V.; Jamshidi-Parsian, Azemat; Phillips, Joshua H.; Fologea, Daniel; Gandy, Jay; Griffin, Robert J. (October 2022, International Journal of Molecular Sciences)

   Targeted delivery of drugs or other therapeutic agents through internal or external triggers has been used to control and accelerate the release from liposomal carriers in a number of studies, but relatively few utilize energy of therapeutic X-rays as a trigger. We have synthesized liposomes that are triggered by ionizing radiation (RTLs) to release their therapeutic payload. These liposomes are composed of natural egg phosphatidylethanolamine (PE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and 1,2-disteroyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG-2000), and the mean size of the RTL was in the range of 114 to 133 nm, as measured by nanoparticle tracking analysis (NTA). The trigger mechanism is the organic halogen, chloral hydrate, which is known to generate free protons upon exposure to ionizing radiation. Once protons are liberated, a drop in internal pH of the liposome promotes destabilization of the lipid bilayer and escape of the liposomal contents. In proof of principle studies, we assessed RTL radiation-release of fluorescent tracers upon exposure to a low pH extracellular environment or exposure to X-ray irradiation. Biodistribution imaging before and after irradiation demonstrated a preferential uptake and release of the liposomes and their cargo at the site of local tumor irradiation. Finally, a potent metabolite of the commonly used chemotherapy irinotecan, SN-38, was loaded into RTL along with near infrared (NIR) fluorescent dyes for imaging studies and measuring tumor cell cytotoxicity alone or combined with radiation exposure, in vitro and in vivo. Fully loaded RTLs were found to increase tumor cell killing with radiation in vitro and enhance tumor growth delay in vivo after three IV injections combined with three, 5 Gy local tumor radiation exposures compared to either treatment modality alone. 

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