Selected Grantee Publications
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- 13 results found
- Cancer
- Stem Cells/Regenerative Medicine
- 2021
HDAC Inhibitor Titration of Transcription and Axolotl Tail Regeneration
Voss et al., Frontiers in Cell and Development Biology. 2021.
https://pubmed.ncbi.nlm.nih.gov/35036404/
New patterns of gene expression are enacted and regulated during tissue regeneration. Romidepsin, an FDA-approved HDAC inhibitor, potently blocks axolotl embryo tail regeneration by altering initial transcriptional responses to injury. Regeneration inhibitory concentrations of romidepsin increased and decreased the expression of key genes. Single-nuclei RNA sequencing at 6 HPA illustrated that key genes were altered by romidepsin in the same direction across multiple cell types. These results implicate HDAC activity as a transcriptional mechanism that operates across cell types to regulate the alternative expression of genes that associate with regenerative success versus failure outcomes. Supported by ORIP (P40OD019794, R24OD010435, R24OD021479), NICHD, and NIGMS.
An NR2F1-Specific Agonist Suppresses Metastasis by Inducing Cancer Cell Dormancy
Khalil et al., The Journal of Experimental Medicine. 2021.
Researchers described the discovery of a nuclear receptor NR2F1 antagonist that specifically activates dormancy programs in malignant cells. Agonist treatment resulted in a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest in multiple human cell lines, as well as patient-derived organoids. This effect was lost when NR2F1 was knocked out. In mice, agonist treatment resulted in inhibition of lung metastasis of head and neck squamous cell carcinomas, even after cessation of the treatment. This work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis. Supported by ORIP (S10OD018522 and S10OD026880) and others.
Integrated Spatial Multiomics Reveals Fibroblast Fate During Tissue Repair
Foster et al., PNAS. 2021.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521719/
The function of regenerative medicine in wound healing remains elusive, partially because of how fibroblasts program and respond to injury remains unclear. Investigators presented a multimodal -omics platform for the comprehensive study of cell populations in complex tissue, which allowed characterization of cells involved in wound healing across time and space. Through integrated analysis of single cell chromatin landscapes and gene expression states, coupled with spatial transcriptomic profiling, fibroblast epigenomes were imputed with temporospatial resolution. This allowed revelation of potential mechanisms controlling fibroblast fate during migration, proliferation, and differentiation following skin injury, and reexamination of the canonical phases of wound healing. Supported by ORIP (S10OD018220) and others.
Limited Expansion of Human Hepatocytes in FAH/RAG2-Deficient Swine
Nelson et al., Tissue Engineering – Part A. 2021.
https://pubmed.ncbi.nlm.nih.gov/34309416/
The mammalian liver's regenerative ability has led researchers to engineer animals as incubators for expansion of human hepatocytes. Nelson et al. engineered immunodeficient swine to support expansion of human hepatocytes and identify barriers to their clinical application. Immunodeficient swine were engineered by knockout of the recombinase-activating gene 2 (RAG2) and fumarylacetoacetate hydrolase (FAH). Immature human hepatocytes (ihHCs) were injected into fetal swine by intrauterine cell transplantation (IUCT) at day 40 of gestation. They identified the mechanism of the eventual graft rejection by the intact NK cell population. They confirmed the presence of residual adaptive immunity in this model of immunodeficiency. Supported by ORIP (U42OD011140).
A Noncoding RNA Modulator Potentiates Phenylalanine Metabolism in Mice
Li et al., Science. 2021.
https://pubmed.ncbi.nlm.nih.gov/34353949/
The role of long noncoding RNAs (lncRNAs) in phenylketonuria (PKU), an inherited disorder causing build-up of an amino acid causing brain problems, is unknown. Investigators demonstrated that the mouse lncRNA Pair and human lncRNA HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited phenotypes that faithfully models human PKU, such as excessive blood phenylalanine (Phe), growth retardation, and progressive neurological symptoms. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes (i.e., that have the capacity to self-renew by dividing). To develop a strategy for restoring liver lncRNAs, these investigators designed lncRNA mimics that exhibit liver enrichment. Treatment with these mimics reduced excessive Phe in Pair -/- and PAH R408W/R408W mice and improved the Phe tolerance of these mice. Supported by ORIP (S10OD012304) and others.
Sexual Dimorphic Impact of Adult-Onset Somatopause on Life Span and Age-Induced Osteoarthritis
Poudel et al., Aging Cell. 2021.
https://pubmed.ncbi.nlm.nih.gov/?term=Poudel%20SB&cauthor_id=34240807
Osteoarthritis (OA) is a major cause of disability worldwide. In humans, the age-associated decline in growth hormone (GH) levels was hypothesized to play a role in the etiology of OA. Investigators studied the impact of adult-onset isolated GH deficiency (AOiGHD) on the life span and skeletal integrity in aged mice. Reductions in GH during adulthood were associated with extended life span and reductions in body temperature in female mice only. However, end-of-life pathology revealed high levels of lymphomas in both sexes, independent of GH status. Skeletal characterization revealed increases in OA severity in AOiGHD mice. In conclusion, while their life span increased, AOiGHD female mice’s health span was compromised by high-grade lymphomas and the development of severe OA. In contrast, AOiGHD males, which did not show extended life span, showed an overall low grade of lymphomas but exhibited significantly decreased health span, evidenced by increased OA severity. Supported by ORIP (S10OD010751) and others.
Advancing Human Disease Research with Fish Evolutionary Mutant Models
Beck et al., Trends in Genetics. 2021.
https://pubmed.ncbi.nlm.nih.gov/34334238/
Model organism research is essential to understand disease mechanisms. However, laboratory-induced genetic models can lack genetic variation and often fail to mimic disease severity. Evolutionary mutant models (EMMs) are species with evolved phenotypes that mimic human disease. They have improved our understanding of cancer, diabetes, and aging. Fish are the most diverse group of vertebrates, exhibiting a kaleidoscope of specialized phenotypes, many that would be pathogenic in humans but are adaptive in the species' specialized habitat. Evolved compensations can suggest avenues for novel disease therapies. This review summarizes current research using fish EMMs to advance our understanding of human disease. Supported by ORIP (R01OD011116), NIA, NIDA, and NIGMS.
Phase Separation Drives Aberrant Chromatin Looping and Cancer Development
Ahn et al., Nature. 2021.
https://doi.org/10.1038/s41586-021-03662-5
How unstructured intrinsically disordered regions (IDRs) contribute to oncogenesis is elusive. Using an Orbitrap fusion tribrid mass spectrometer, investigators show that IDRs contained within NUP98–HOXA9, a homeodomain-containing transcription factor chimera recurrently detected in leukaemias, are essential for establishing liquid–liquid phase separation (LLPS) puncta of chimera and for inducing leukaemic transformation. LLPS of NUP98–HOXA9 not only promotes chromatin occupancy of chimera transcription factors, but also is required for the formation of a broad “super-enhancer”-like binding pattern typically seen at leukaemogenic genes, which potentiates transcriptional activation. An artificial HOX chimera, created by replacing the phenylalanine and glycine repeats of NUP98 with an unrelated LLPS-forming IDR of the FUS protein, had similar enhancing effects on the genome-wide binding and target gene activation of the chimera. This report describes a proof-of-principle example in which cancer acquires mutation to establish oncogenic transcription factor condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumor transformation. Supported by ORIP (S10OD018445).
Single-Cell Protein Activity Analysis Identifies Recurrence-Associated Renal Tumor Macrophages
Obradovic et al., Cell. 2021.
https://doi.org/10.1016/j.cell.2021.04.038
Post-surgery course of clear cell renal carcinoma (ccRCC) is mixed because of the heterogeneity of the disease. Using high-performance computing cluster and storage systems, investigators established an inclusive ccRCC tumor microenvironment (TME) map by using single-cell RNA sequencing data of subpopulations of tumor and tumor-adjacent tissues. Analysis of the data identified key TME subpopulations as well as their master regulators and candidate cell-cell interactions, revealing clinically relevant cell populations. Specifically, the study uncovered a tumor-specific macrophage subpopulation, validated by spatially resolved, quantitative multispectral immunofluorescence. In a large clinical validation cohort, markers of this subpopulation were significantly enriched in tumors from patients who recurred following surgery. Supported by ORIP (S10OD012351, S10OD021764) and others.
Postpubertal Spermatogonial Stem Cell Transplantation Restores Functional Sperm Production in Rhesus Monkeys Irradiated Before and After Puberty
Shetty et al., Andrology. 2021.
https://onlinelibrary.wiley.com/doi/10.1111/andr.13033
Cancer treatment of prepubertal patients impacts future fertility due to the abolition of spermatogonial stem cells (SSCs). Prepubertal rhesus monkeys (n=6) were unilaterally castrated, and the remaining testes irradiated twice to insure loss of SSCs; the animals were treated with a vehicle or GnRH antagonist for 8 weeks (n=3/treatment). The cryopreserved prepubertal testicular tissue was allergenically transplanted into the intact testes of the monkeys after puberty. Recovery of viable donor epididymal sperm was observed in half the monkeys. These results illustrate that sperm production can be restored in primates by transplantation of testicular cells from cryopreserved untreated prepubertal testes into seminiferous tubules of the remaining testes. Supported by ORIP (P51OD011092), NICHD, and NCI.