A5055574198- Cancer-related molecular mechanisms research
- RNA modifications and cancer
- Sarcoma Diagnosis and Treatment
- Ferroptosis and cancer prognosis
- Glioma Diagnosis and Treatment
- Circular RNAs in diseases
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Lung Cancer Treatments and Mutations
- RNA Research and Splicing
- Cancer Genomics and Diagnostics
- DNA Repair Mechanisms
- Cancer Immunotherapy and Biomarkers
- Liver Disease Diagnosis and Treatment
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- RNA and protein synthesis mechanisms
- Pancreatic and Hepatic Oncology Research
- Cancer Cells and Metastasis
- Ovarian cancer diagnosis and treatment
- Cancer therapeutics and mechanisms
- Pancreatic function and diabetes
- Microtubule and mitosis dynamics
- Polyomavirus and related diseases
- PI3K/AKT/mTOR signaling in cancer
- Cancer Mechanisms and Therapy
Michigan Center for Translational Pathology
2013-2024
University of Michigan–Ann Arbor
2015-2024
Michigan Medicine
2017-2022
U-M Rogel Cancer Center
2020
Michigan United
2013-2019
Translational Research in Oncology
2014
Ann Arbor Center for Independent Living
2014
The rate of transcription elongation plays an important role in the timing expression full-length transcripts as well regulation alternative splicing. In this study, we coupled Bru-seq technology with 5,6-dichlorobenzimidazole 1-β-D-ribofuranoside (DRB) to estimate rates over 2000 individual genes human cells. This technique, BruDRB-seq, revealed gene-specific differences a median around 1.5 kb/min. We found that rapid showed higher densities H3K79me2 and H4K20me1 histone marks compared...
AMP-activated protein kinase (AMPK) senses energetic stress and, in turn, promotes catabolic and suppresses anabolic metabolism coordinately to restore energy balance. We found that a diverse array of AMPK activators increased mTOR complex 2 (mTORC2) signaling an AMPK-dependent manner cultured cells. Activation with the type diabetes drug metformin (GlucoPhage) also mTORC2 liver vivo primary hepatocytes manner. AMPK-mediated activation did not result from suppression mTORC1 thus reduced...
Abstract Cancer metabolism is rewired to support cell survival in response intrinsic and environmental stressors. Identification of strategies target these adaptions an area active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway pancreatic cancer used maintain redox balance. Here, we sought identify metabolic dependencies following GOT1 inhibition exploit this feature provide additional insight into regulation metabolism. Using pharmacological...
Gangliosides have been shown to be plasma membrane receptors for both murine polyomavirus and SV40, while JC virus uses serotonin receptors. In contrast, little is known of the receptor entry pathway BK (BKV), which can cause severe disease in immunosuppressed bone marrow renal transplant patients. Using sucrose flotation assays, we investigated BKV binding interaction with human erythrocyte membranes determined that this was dependent on a neuraminidase-sensitive, proteinase K-resistant...
The mammalian target of rapamycin complex 1 (mTORC1) functions as an environmental sensor to promote critical cellular processes such protein synthesis, cell growth, and proliferation in response growth factors nutrients. While diverse stimuli regulate mTORC1 signaling, the direct molecular mechanisms by which senses responds these signals remain poorly defined. Here we investigated role mTOR phosphorylation function. By employing mass spectrometry phospho-specific antibodies, demonstrated...
Abstract Of the many types of DNA damage, double-strand breaks (DSBs) are probably most deleterious. Mounting evidence points to an intricate relationship between DSBs and transcription. A cell system in which impact on transcription can be investigated at precisely mapped genomic is essential study this relationship. Here a human line, we map genome-wide high resolution induced by restriction enzyme, characterize their gene expression four independent approaches monitoring steady-state RNA...
T cell proliferation and cytokine production are bioenergetically biosynthetically costly. The inability to meet these metabolic demands results in altered differentiation, accompanied by impaired effector function, attrition of the immune response. Interleukin-17–producing CD4 cells (T H 17s) mediators host defense, autoimmunity, antitumor immunity setting adoptive therapy. 17s long-lived that require mitochondrial oxidative phosphorylation (OXPHOS) for function vivo. Considering polarized...
The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis a human PCSC-enriched gene signature, we identified transcription factor HNF1A as putative regulator PCSC function. Levels its target genes were found to be elevated in PCSCs tumorspheres, depletion resulted growth inhibition, apoptosis, impaired tumorsphere formation, decreased marker expression, downregulation POU5F1/OCT4...
Common fragile sites (CFSs) are regions susceptible to replication stress and hotspots for chromosomal instability in cancer. Several features were suggested underlie CFS instability, however, these prevalent across the genome. Therefore, molecular mechanisms underlying remain unclear. Here, we explore transcriptional profile DNA timing (RT) under mild context of 3D genome organization. The results reveal a fragility signature, comprised TAD boundary overlapping highly transcribed large gene...
Cyclin-dependent kinases 12/13 play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Biallelic CDK12 loss has been documented various malignancies. Here, we develop a selective CDK12/13 PROTAC degrader, YJ9069, which effectively inhibits proliferation subsets prostate cancer cells preferentially over benign immortalized cells. degradation rapidly triggers gene-length-dependent transcriptional elongation defects, leading to...
The nonenveloped polyomavirus (Py) traffics from the plasma membrane to endoplasmic reticulum (ER), where it penetrates ER membrane, allowing viral genome reach nucleus cause infection. mechanism of penetration for Py, and other viruses, remains poorly characterized. We showed previously that chaperone ERp29 alters conformation Py coat protein VP1, enabling virus interact with membranes. Here, we developed a perforation assay ERp29-activated perforates physiologically relevant an event...
The polycomb proteins BMI-1 and EZH2 are highly overexpressed by Ewing sarcoma (ES), a tumor of stem cell origin that is driven EWS-ETS fusion oncogenes, most commonly EWS-FLI1. In the current study we analyzed expression transcription programs controlled during embryonic development to determine if they abnormal in ES. Our results show target gene ES deviates from normal tissues cells that, as expected, targets relatively repressed. However, also discovered paradoxical up regulation...
Abstract Developmental transcription programs are epigenetically regulated by multi‐protein complexes, including the menin‐ and MLL‐containing trithorax (TrxG) which promote gene depositing H3K4me3 activating mark at target promoters. We recently reported that in Ewing sarcoma, MLL1 (lysine methyltransferase 2A, KMT2A) menin overexpressed function as oncogenes. Small molecule inhibition of menin–MLL interaction leads to loss protein expression, growth tumorigenicity. Here, we have...
In response to ionizing radiation (IR), cells activate a DNA damage (DDR) pathway re-program gene expression. Previous studies using total cellular RNA analyses have shown that the stress kinase ATM and transcription factor p53 are integral components required for induction of IR-induced These did not distinguish between changes in synthesis turnover address role enhancer elements DDR-mediated transcriptional regulation. To determine contribution degradation monitor activity following...
Abstract Purpose: Propagation of Ewing sarcoma requires precise regulation EWS::FLI1 transcriptional activity. Determining the mechanisms fusion will advance our understanding tumor progression. Here we investigated whether HOXD13, a developmental transcription factor that promotes metastatic phenotypes, influences Experimental Design: Existing and cell line datasets were used to define binding sites targets. Chromatin immunoprecipitation CRISPR interference employed identify enhancers....
Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism
The anti-cancer drug camptothecin inhibits replication and transcription by trapping DNA topoisomerase I (Top1) covalently to in a "cleavable complex". To examine the effects of on RNA synthesis genome-wide we used Bru-Seq show that treatment primarily affected elongation. We also observed increased reads past termination sites as well at enhancer elements. Following removal camptothecin, spread wave from 5'-end genes with no recovery apparent polymerases stalled body genes. As result,...
Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 mutated more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental studies the contribution individual genes to carcinogenesis. Oncogenic Kras occur early during carcinogenesis and are considered an initiating event. In contrast, p53 later tumor progression. our model, we recapitulated order disease, with mutation following expression...
Wnt/β-catenin signaling is active in small subpopulations of Ewing sarcoma cells, and these cells display a more metastatic phenotype, part due to antagonism EWS-FLI1-dependent transcriptional activity. Importantly, β-catenin-activated also alter secretion extracellular matrix (ECM) proteins. We thus hypothesized that, addition cell-autonomous mechanisms, Wnt/β-catenin-active tumor might contribute disease progression by altering the microenvironment (TME). Analysis transcriptomic data from...
Although KMT2D, also known as MLL2, is to play an essential role in development, differentiation, and tumor suppression, its pancreatic cancer development not well understood. Here, we discovered a novel signaling axis mediated by which links TGF-β the activin A pathway. We found that upregulates microRNA, miR-147b, turn leads post-transcriptional silencing of KMT2D. Loss KMT2D induces expression secretion A, activates noncanonical p38 MAPK-mediated pathway modulate cell plasticity, promote...
H3K27M diffuse midline gliomas (DMG), including intrinsic pontine (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like AC-like phenotypes perform transcriptomics, metabolomics, bioenergetic profiling to identify metabolic programs the different states. We then define strategies target vulnerabilities within...