Selected Grantee Publications
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- 99 results found
- Cancer
- Pediatrics
p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
Faget et al., Cancer Discovery. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/
This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.
Simultaneous Evaluation of Treatment Efficacy and Toxicity for Bispecific T-Cell Engager Therapeutics in a Humanized Mouse Model
Yang et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300040R
Immuno-oncology–based therapies are an evolving powerful treatment strategy that targets the immune system and harnesses it to kill tumor cells directly. Investigators describe the novel application of a humanized mouse model that can simultaneously evaluate the efficacy of bispecific T cell engagers to control tumor burden and the development of cytokine release syndrome. The model also captures variability in responses for individual patients. Supported by ORIP (R24OD026440), NIAID, NCI, and NIDDK.
A LGR5 Reporter Pig Model Closely Resembles Human Intestine for Improved Study of Stem Cells in Disease
Schaaf et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300223R
The constant epithelial regeneration in the intestine is the sole responsibility of intestinal epithelial stem cells (ISCs), which reside deep in the intestinal crypt structures. To effectively study ISCs, tools to identify this cell population are necessary. This study validates ISC isolation in a new porcine Leucine Rich Repeat Containing G Protein–Coupled Receptor 5 (LGR5) reporter line and demonstrates the use of these pigs as a novel colorectal cancer model. Overall, this novel porcine model provides critical advancement to the field of translational gastrointestinal research. Supported by ORIP (R21OD019738, K01OD019911), NCI, and NIDDK.
Early Detection of Pseudocapillaria tomentosa by qPCR in Four Lines of Zebrafish, Danio rerio (Hamilton 1882)
Schuster et al., Journal of Fish Diseases. 2023.
https://onlinelibrary.wiley.com/doi/10.1111/jfd.13773
The intestinal nematode Pseudocapillaria tomentosa in zebrafish (Danio rerio) causes profound intestinal lesions, emaciation, and death and is a promoter of a common intestinal cancer in zebrafish. This nematode has been detected in an estimated 15% of zebrafish laboratories. Adult worms are readily detected about 3 weeks after exposure by either histology or wet mount preparations of the intestine, and larval worms are inconsistently observed in fish before this time. A quantitative PCR (qPCR) test was recently developed to detect the worm in fish and water, and here the authors determined that the test on zebrafish intestines was effective for earlier detection. Supported by ORIP (R24OD010998, P40OD011021).
Effects of Acute Femoral Head Ischemia on the Growth Plate and Metaphysis in a Piglet Model of Legg-Calvé-Perthes Disease
Armstrong et al., Osteoarthritis and Cartilage. 2023.
https://pubmed.ncbi.nlm.nih.gov/36696941/
Legg-Calvé-Perthes disease (LCPD) can lead to permanent deformity of the femoral head and premature osteoarthritis, but the underlying cause remains unknown. More work is needed to determine optimal treatment methods for LCPD. Using a piglet model for LCPD, researchers assessed the effects of acute femoral head ischemia on the proximal femoral growth plate and metaphysis. They reported that alterations to the growth plate zones and metaphysis occurred by 2 days post-ischemia and persisted at 7 days post-ischemia. These findings suggest that growth disruption may occur sooner after the onset of ischemia than researchers had hypothesized previously. Supported by ORIP (T32OD010993, K01OD021293), NIAMS, and NCATS.
Infection of the Maternal–Fetal Interface and Vertical Transmission Following Low-Dose Inoculation of Pregnant Rhesus Macaques (Macaca mulatta) with an African-Lineage Zika Virus
Koenig et al., PLOS ONE. 2023.
https://doi.org/10.1371/journal.pone.0284964
Researchers examined transmission of Zika virus to nonhuman primate fetuses during pregnancy. Even with a low dosage of inoculation of the dams, the investigators found that the Zika virus infected fetuses, despite the presence of a “placental fortress,” which normally protects fetuses during gestation. This transmission illustrates the high level of infectivity threat that Zika poses, which may increase if mosquitoes expand their global habitats. Understanding how Zika breaches the placental barrier will help researchers develop strategies to prevent fetal infection during pregnancy and thereby prevent adverse outcomes, such as brain malformation defects. Supported by ORIP (P51OD011106, S10OD023526), NIAID, NCI, and NIGMS.
Using Mass Spectrometry Imaging to Map Fluxes Quantitatively in the Tumor Ecosystem
Schwaiger-Haber et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/37208361/
Mass spectrometry imaging (MSI) can be used to identify metabolic patterns within different microenvironments of tumors but has not been fully integrated into metabolomics workflows. Investigators developed an integrated approach by combining MSI, stable isotope labeling, and a spatial variant of Isotopologue Spectral Analysis to study metabolic pathways across the brains of mice harboring GL261 glioma, a mouse model for glioblastoma. This study reveals the importance of multiple anabolic pathways, including fatty acid elongation flux, in glioma. Supported by ORIP (R24OD024624).
Therapeutic Blocking of VEGF Binding to Neuropilin-2 Diminishes PD-L1 Expression to Activate Antitumor Immunity in Prostate Cancer
Wang et al., Science Translational Medicine. 2023.
Prostate cancers often escape immune detection and destruction. Investigators report that neuropilin-2 (NRP2), which functions as a vascular endothelial growth factor (VEGF) receptor on tumor cells, is an attractive target to activate antitumor immunity in prostate cancer. They found that NRP2 depletion increased T cell activation in vitro. Additionally, inhibition of the binding of VEGF to NRP2 using a mouse-specific anti-NRP2 monoclonal antibody resulted in necrosis and tumor regression. These findings provide justification for the initiation of clinical trials using this function-blocking antibody in treatment of prostate cancer, especially for patients with aggressive disease. Supported by ORIP (R24OD026440) and NCI.
Giardia Hinders Growth by Disrupting Nutrient Metabolism Independent of Inflammatory Enteropathy
Giallourou et al., Nature Communications. 2023.
https://www.nature.com/articles/s41467-023-38363-2
Giardia lamblia is one of the most common intestinal pathogens among children in low- and middle-income countries. Investigators performed translational investigations using the Malnutrition and Enteric Diseases (MAL-ED) male and female cohort, as well as mice of both sexes, to identify mechanistic pathways that might explain Giardia-induced effects on early childhood growth. They identified signatures in the urinary metabolome of young children, suggesting that host growth restriction during infection is mediated by dysregulated amino acid metabolism. Supported by ORIP (P40OD010995), NIAID, and NIDDK.
The Incompetence of Mosquitoes—Can Zika Virus Be Adapted to Infect Culex tarsalis Cells?
Gallichotte et al., mSphere . 2023.
Zika virus (ZIKV) is transmitted between humans by Aedes aegypti mosquitoes. However, the 2015 to 2017 outbreak raised questions regarding the role of Culex species mosquitoes in transmission. Investigators attempted to adapt ZIKV to C. tarsalis by serially passaging the virus on cocultured A. aegypti and C. tarsalis cells to identify viral determinants of species specificity. Next-generation sequencing of cocultured virus passages revealed variants of interest that were engineered into nine recombinant viruses. None of these viruses showed increased infection of Culex cells or mosquitoes. Thus, although ZIKV might infect Culex mosquitoes occasionally, Aedes mosquitoes likely drive transmission and human risk. Supported by ORIP (T32OD010437) and NIAID.