Selected Grantee Publications
A Novel Auxin-Inducible Degron System for Rapid, Cell Cycle–Specific Targeted Proteolysis
Capece et al., Cell Death and Differentiation. 2023.
https://www.nature.com/articles/s41418-023-01191-4
The discrimination of protein biological functions in different phases of the cell cycle is limited by the lack of experimental approaches that do not require pre-treatment with compounds affecting the cell-cycle progression. Therefore, potential cycle-specific biological functions of a protein of interest could be biased by the effects of cell treatments. The OsTIR1/auxin-inducible degron (AID) system allows “on-demand” selective and reversible protein degradation upon exposure to the phytohormone auxin. However, this technology does not allow researchers to study the effect of acute protein depletion selectively in one phase of the cell cycle, as auxin similarly affects all the treated cells irrespective of their proliferation status. Therefore, the AID system requires coupling with cell synchronization techniques, which can alter the basal biological status of the studied cell population, as with previously available approaches. Here, the investigators introduce the Regulate OsTIR1 Levels based on the Cell Cycle Status (ROLECCS) system, which induces proteolysis of both exogenously transfected and endogenous gene-edited targets in specific phases of the cell cycle. They propose the use of the ROLECCS system as a new and improved way of studying the differential roles that target proteins may have in specific phases of the cell cycle. Supported by ORIP (K01OD031811) and NCI.
Baseline Tumor Gene Expression Signatures Correlate With Chemoimmunotherapy Treatment Responsiveness in Canine B Cell Lymphoma
Dittrich et al., PLOS ONE. 2023.
https://pubmed.ncbi.nlm.nih.gov/37624862/
Pet dogs develop spontaneous diffuse large B cell lymphoma (DLBCL), and veterinary clinical trials have been employed to treat canine DLBCL and to inform clinical trials for their human companions. Investigators evaluated gene expression in lymph node aspirates from 18 trial dogs and defined good responders as those who relapsed after 90 days, and poor responders as those who relapsed prior to 90 days. They found increased CCND3 correlated with poor prognosis and increased CD36 correlated with good prognosis, as is observed in humans. These findings identify biomarkers that may help guide the choice of chemoimmunotherapy treatment in dogs. Supported by ORIP (K01OD028268) and NCI.
Intestinal Microbiota Controls Graft-Versus-Host Disease Independent of Donor–Host Genetic Disparity
Koyama et al., Immunity. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480848/
Allogeneic hematopoietic stem cell transplantation is a curative therapy for hematopoietic malignancies and non-malignant diseases, but acute graft-versus-host disease (GVHD) remains a serious complication. Specifically, severe gut GVHD is the major cause of transplant-related mortality. Here, the authors show that genetically identical mice, sourced from different vendors, had distinct commensal bacterial compositions, which resulted in significantly discordant severity in GVHD. These studies highlight the importance of pre-transplant microbiota composition for the initiation and suppression of immune-mediated pathology in the gastrointestinal tract, demonstrating the impact of non-genetic environmental determinants to transplant outcome. Supported by ORIP (S10OD028685), NIA, NCI, and NHLBI.
Assessment of Various Standard Fish Diets on Gut Microbiome of Platyfish Xiphophorus maculatus
Soria et al., Journal of Experimental Zoology Part B. 2023.
https://onlinelibrary.wiley.com/doi/10.1002/jez.b.23218
Diet is an important factor affecting experimental reproducibility and data integration across studies. Reference diets for nontraditional animal models are needed to control diet-induced variation. In a study of the dietary impacts on the gut microbiome, researchers found that switching from a custom diet to a zebrafish diet altered the Xiphophorus gut microbiome. Their findings suggest that diets developed specifically for zebrafish can affect gut microbiome composition and might not be optimal for Xiphophorus. Supported by ORIP (R24OD011120, R24OD031467, P40OD011021) and NCI.
A Germ-Free Humanized Mouse Model Shows the Contribution of Resident Microbiota to Human-Specific Pathogen Infection
Wahl et al., Nature Biotechnology. 2023.
https://www.nature.com/articles/s41587-023-01906-5
Germ-free (GF) mice are of limited value in the study of human-specific pathogens because they do not support their replication. In this report, investigators developed a GF humanized mouse model using the bone marrow–liver–thymus platform to provide a robust and flexible in vivo model that can be used to study the role of resident microbiota in human health and disease. They demonstrated that resident microbiota promote viral acquisition and pathogenesis by using two human-specific pathogens, Epstein–Barr virus and HIV. Supported by ORIP (P40OD010995), FIC, NIAID, NCI, and NIDDK.
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.
Lymph-Node-Based CD3+ CD20+ Cells Emerge From Membrane Exchange Between T Follicular Helper Cells and B Cells and Increase Their Frequency Following Simian Immunodeficiency Virus Infection
Samer et al., Journal of Virology. 2023.
https://www.doi.org/10.1128/jvi.01760-22
CD4+ T follicular helper cells are known to persist during antiretroviral therapy (ART) and have been identified as key targets for viral replication and persistence. Researchers identified a lymphocyte population that expresses CD3 (i.e., T cell lineage marker) and CD20 (i.e., B cell lineage marker) on the cellular surface in lymphoid tissues from rhesus macaques of both sexes and humans of male and female sexes. In macaques, the cells increased following simian immunodeficiency virus infection, were reduced with ART, and increased in frequency after ART interruption. These cells represent a potential area for future therapeutic strategies. Supported by ORIP (P51OD011132, U42OD011023), NIAID, NCI, NIDDK, NIDA, NHLBI, and NINDS.
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.