A5084045965- Renal and related cancers
- Cancer Genomics and Diagnostics
- Biosimilars and Bioanalytical Methods
- Cancer, Hypoxia, and Metabolism
- Biological Research and Disease Studies
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Plant nutrient uptake and metabolism
- Adrenal and Paraganglionic Tumors
- Renal cell carcinoma treatment
- Genomics and Chromatin Dynamics
- Biomedical Ethics and Regulation
- Supramolecular Self-Assembly in Materials
- Organ Transplantation Techniques and Outcomes
- Thermal Regulation in Medicine
- Bacteriophages and microbial interactions
- Multiple and Secondary Primary Cancers
- Immune cells in cancer
- RNA modifications and cancer
- Antimicrobial Peptides and Activities
- Genetic and Kidney Cyst Diseases
- Adenosine and Purinergic Signaling
- COVID-19 Clinical Research Studies
- Mitochondrial Function and Pathology
- MRI in cancer diagnosis
University of Oxford
2020-2024
Ludwig Cancer Research
2024
Highlights•Hypoxia downregulates SARS-CoV-2 receptors ACE2 and TMPRSS2 inhibits viral entry•Hypoxic signaling replication particle genesis via HIF-1α•HIF prolyl hydroxylase inhibitors are a potential therapeutic option for COVID-19SummaryCOVID-19, caused by the novel coronavirus SARS-CoV-2, is global health issue with more than 2 million fatalities to date. Viral shaped cellular microenvironment, one important factor consider oxygen tension, in which hypoxia inducible (HIF) regulates...
Amplification of the mitotic kinase Aurora A or loss its regulator protein phosphatase 6 (PP6) have emerged as drivers genome instability. Cells lacking PPP6C, catalytic subunit PP6, amplified activity, and we show here, enlarged spindles which fail to hold chromosomes tightly together in anaphase, causing defective nuclear structure. Using functional genomics shed light on processes underpinning these changes, discover synthetic lethality between PPP6C kinetochore NDC80. We find that NDC80...
Defining the initial events in oncogenesis and cellular responses they entrain, even advance of morphologic abnormality, is a fundamental challenge understanding cancer initiation. As paradigm to address this, we longitudinally studied changes induced by loss tumor suppressor gene von Hippel Lindau (VHL), which ultimately drives clear cell renal carcinoma. Vhl inactivation was directly coupled expression tdTomato reporter within single allele, allowing accurate visualization affected cells...
Despite a general role for the HIF hydroxylase system in cellular oxygen sensing and tumour hypoxia, cancer-associated mutations of genes this pathway, including PHD2, PHD1, EPAS1 (encoding HIF-2α) are highly tissue-restricted, being observed pseudohypoxic pheochromocytoma paraganglioma (PPGL) but rarely, if ever, other tumours. In an effort to understand that paradox gain insights into pathogenesis PPGL, we constructed mice which principal prolyl hydroxylase, Phd2, is inactivated adrenal...
Abstract The von Hippel Lindau (VHL) tumor suppressor gene is a classical whose biallelic inactivation truncal event in clear cell renal carcinoma (ccRCC) evolution. VHL best characterized as the recognition component of an E3 ubiquitin ligase complex that targets hypoxia inducible transcription factors (HIF1A and HIF2A) for conditional oxygen-dependent degradation. HIF activation following early ccRCC progression. While functions HIF1A HIF2A biology progression have been studied, those...
Abstract Characterizing the early events preceding tumorigenesis is a major challenge in understanding cancer. To address this, we are investigating paradigm of clear cell renal carcinoma (ccRCC) that driven by biallelic loss von Hippel Lindau (VHL) tumor suppressor gene. Though VHL required, additional mutations have been found evolution cancer, most commonly Polybromo-1 (PBRM1), subunit PBAF SWI/SNF chromatin remodeling complex. Concomitant Vhl and Pbrm1 deletion, but not deletion alone,...
<p><i>Vhl</i>-null cells exhibit time-dependent proliferation and association with ccRCC-like gene expression. <b>A,</b> Representative dual IHC for tdTomato (brown) Ki67 (purple) counterstained hematoxylin in kidneys of KO mice harvested early after recombination. Scale bar, 25 μm. Magnification, ×40. Black arrow, dual-positive cell; red tdTomato-negative Ki67-positive cell. <b>B,</b> Proportion tdTomato-positive (top) or (bottom) that are positive...
<p>Renal cortex, but not the papilla, is permissive to long-term survival of <i>Vhl</i>-null cells. <b>A,</b> Representative tdTomato IHC counterstained with hematoxylin in different renal anatomical regions Control or KO mice harvested at early late time points. Scale bar, 100 μm. Magnification, ×20. <b>B,</b> Proportion cells that are tdTomato-positive kidney as quantified by kidneys from intervals after recombination. <i>n</i> = 7F,...
<p>Vhl-null cells specifically undergo time-dependent alterations in gene expression</p>
<p>Biallelic Vhl loss entrains early cell-specific transcriptomic changes in renal tubular cells</p>
<p><i>Vhl</i>-null cells specifically undergo time-dependent alterations in gene expression. <b>A,</b> Density plot depicting UMAP distribution of tdTomato-positive from kidneys Control and KO mice harvested at the early or late time points. <b>B,</b> Left, points colored by cluster. Right, proportion each condition belonging to any <b>C,</b> Scatter frequency expression point against log<sub>2</sub>-fold change...
<p>Biallelic <i>Vhl</i> inactivation entrains early cell-specific transcriptomic changes in RTE cells. <b>A,</b> Density plot depicting UMAP distribution of tdTomato-negative and -positive cells from kidneys Control KO mice harvested after recombination. <b>B,</b> Left, recombination colored by clusters. Right, proportion each condition belonging to any cluster. <b>C,</b> Scatter frequency expression (top) or tdTomato-positive (bottom)...
<p><i>Vhl</i>-null cells specifically undergo time-dependent alterations in gene expression. <b>A,</b> Density plot depicting UMAP distribution of tdTomato-positive from kidneys Control and KO mice harvested at the early or late time points. <b>B,</b> Left, points colored by cluster. Right, proportion each condition belonging to any <b>C,</b> Scatter frequency expression point against log<sub>2</sub>-fold change...
<p>A novel reporter model for <i>Vhl</i> inactivation in the mouse kidney. <b>A,</b> Design and recombination of cell marking conditional <i>Vhl<sup>pjr</sup></i> allele. Double single arrows indicate reversible irreversible processes, respectively. <i>Vhl<sup>pjr.fl</sup>, Vhl<sup>pjr.inrec</sup></i>, <i>Vhl<sup>pjr.KO</sup></i> refer to “floxed,” “incompletely recombined,”...
<p>Renal cortex, but not the papilla, is permissive to long-term survival of <i>Vhl</i>-null cells. <b>A,</b> Representative tdTomato IHC counterstained with hematoxylin in different renal anatomical regions Control or KO mice harvested at early late time points. Scale bar, 100 μm. Magnification, ×20. <b>B,</b> Proportion cells that are tdTomato-positive kidney as quantified by kidneys from intervals after recombination. <i>n</i> = 7F,...
<p>scRNA-seq on flow-sorted renal cells. <b>A,</b> UMAP plot of tdTomato-negative (left) or tdTomato-positive cells (right) from kidneys Control mice harvested at the early time point. Cells are colored by inferred cell type. LoH, loop Henle; DCT, distal convoluted tubule; CD, collecting duct; PC, principal cell; IC, intercalated; PEC, parietal epithelial VSMC, vascular smooth muscle NK, natural killer cell. <b>B,</b> Proportion sequenced to be each type in...
<p>Single-cell RNA sequencing on flow-sorted renal cells</p>
<p>A novel reporter model for <i>Vhl</i> inactivation in the mouse kidney. <b>A,</b> Design and recombination of cell marking conditional <i>Vhl<sup>pjr</sup></i> allele. Double single arrows indicate reversible irreversible processes, respectively. <i>Vhl<sup>pjr.fl</sup>, Vhl<sup>pjr.inrec</sup></i>, <i>Vhl<sup>pjr.KO</sup></i> refer to “floxed,” “incompletely recombined,”...
<p>Biallelic <i>Vhl</i> inactivation entrains early cell-specific transcriptomic changes in RTE cells. <b>A,</b> Density plot depicting UMAP distribution of tdTomato-negative and -positive cells from kidneys Control KO mice harvested after recombination. <b>B,</b> Left, recombination colored by clusters. Right, proportion each condition belonging to any cluster. <b>C,</b> Scatter frequency expression (top) or tdTomato-positive (bottom)...
<p>Vhl-null cells specifically undergo time-dependent alterations in gene expression</p>
<p><i>Vhl</i>-null cells exhibit time-dependent proliferation and association with ccRCC-like gene expression. <b>A,</b> Representative dual IHC for tdTomato (brown) Ki67 (purple) counterstained hematoxylin in kidneys of KO mice harvested early after recombination. Scale bar, 25 μm. Magnification, ×40. Black arrow, dual-positive cell; red tdTomato-negative Ki67-positive cell. <b>B,</b> Proportion tdTomato-positive (top) or (bottom) that are positive...
<p>Biallelic Vhl loss entrains early cell-specific transcriptomic changes in renal tubular cells</p>