Project description:Tumor-associated neutrophils (TANs) are an under-characterized population in glioblastoma. We use scRNA-seq to explore phenotypic diversity among these cells.
Project description:Epigenome analysis of skull base chordoams Genome wide DNA methylation profiling of 46 skull base chordomas. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 450,000 CpGs in skull base chorodma samples. Samples included 46 skull base chorodmas
Project description:The prognostic factors of skull base chordoma associated with outcomes of patients after surgical resection remain poorly defined. This project aimed to identify a novel prognostic factor for patients with skull base chordoma. Using a proteomics approach, we screened tumor biomarkersthat upregulated in the rapid-recurrence group of chordoma, narrowed down by bioinformatics analysis, and finally potential biomarker was chosen for validation by immunohistochemistry using tissue microarray.
Project description:We have previously shown that skull bone marrow derived myeloid cells are different from their blood derived counterparts. Whether or not cues from the CNS microenvironment differentially shape the skull bone marrow niche relative to peripheral bone marrow niches is unknown. To test this, we performed scRNAseq of skull and peripheral bone marrow niches.
Project description:Necrosis is commonly found in various solid tumors and predicts worse outcome. Chronic ischemia can initiate tumor necrosis, but how the damaged tissue further expands is unclear. Previous studies found that neutrophils associate with necrosis and could contribute to necrosis development in glioblastoma (GBM) by transferring myeloperoxidase (MPO)-containing granules into tumor cells and inducing tumor cell ferroptosis. How the neutrophilic granule transfer occurs is unknown. Here, through an unbiased small molecule screen, we found that statins can inhibit neutrophil-induced tumor cell death by blocking the neutrophilic content transfer into tumor cells. Surprisingly, we found that neutrophils are engulfed by tumor cells before they are fragmented and release the MPO-containing contents in tumor cells. This process involves LC3-associated phagocytosis (LAP) and can be blocked by inhibiting the Vps34-UVRAG-containing PI3K complex. Inhibition of MPO or depletion of Vps34 in an orthotopic xenograft GBM mouse model reduced necrosis formation and allowed tumor-bearing mice to survive longer. Therefore, this study revealed that the neutrophilic granule transfer involves LAP-mediated neutrophil internalization, which then triggers tumor ferroptotic cell death in glioblastoma. Blocking this process may improve prognosis of GBM.
Project description:We used single cell RNA sequencing to profile the immune cell repertoire of tumor tissue, peripheral blood mononuclear cells (PBMC), bone marrow mononuclear cells (BMMC) from distal bone and cranial (skull) bone from human treatment-naive glioblastoma patients. For comparison, we obtained and analyzed control samples (cranial bone and PBMC) from human non-malignant intracranial disease.
Project description:The bone marrow microenvironment is a critical regulator of hematopoietic stem cell self-renewal and fate. While it is appreciated that aging, chronic inflammation and other insults compromise bone marrow function and thereby negatively affect hematopoiesis, it is not known whether different bone compartments exhibit distinct microenvironmental properties and functional resilience. Here, we have employed imaging, pharmacological approaches, and mouse genetics to uncover specialized and highly surprising properties of bone marrow in adult and aging skull. Specifically, we show that the skull bone marrow undergoes lifelong expansion involving vascular growth, which results in an increasing contribution to total hematopoietic output. Furthermore, skull is largely protected against major hallmarks of aging, including upregulation of pro-inflammatory cytokines, adipogenesis and loss of vascular integrity. Striking dynamic and rapid changes to the skull vasculature and bone marrow are induced by physiological alterations, namely pregnancy, but also pathological challenges, such as stroke and experimental chronic myeloid leukemia. These responses are highly distinct from femur, the most extensively studied bone marrow compartment. We propose that skull harbors a protected and dynamically expanding bone marrow microenvironment, which is relevant for experimental studies but, potentially, also clinical treatments in humans.
Project description:COVID-19 has been associated with a variety of neurological symptoms, including brain fog and brain tissue loss. This raises concerns about the virus's acute and potential chronic impacts on the brain. Using whole mouse and human tissue clearing, we determined all potential tissues targeted by the SARS-CoV-2 and showed that the spike protein accumulates in the skull-meninges-brain axis in both mice and humans. Injection of the spike protein into the mouse skull alone was sufficient to cause cell death in the brain. Notably, we found spike protein in the skull of ~60% of deceased people who had COVID-19 in the past. Mass spectrometry-based proteomics in mice and humans revealed dysregulated inflammatory and vascular pathways throughout tissues in the skull-meninges-brain axis. Overall, SARS-CoV-2 spike protein accumulation in the CNS borders might be involved in the immediate and long-term consequences in the brain parenchyma, and this may present diagnostic and therapeutic opportunities.