A5088225640- Adipose Tissue and Metabolism
- Cancer Cells and Metastasis
- Adipokines, Inflammation, and Metabolic Diseases
- Cardiovascular Disease and Adiposity
- Pancreatic and Hepatic Oncology Research
- Cancer, Lipids, and Metabolism
- Cancer, Hypoxia, and Metabolism
- Mesenchymal stem cell research
- Lipid metabolism and biosynthesis
- Phagocytosis and Immune Regulation
- Cellular transport and secretion
- Cancer Research and Treatments
- Cell Adhesion Molecules Research
- Exercise and Physiological Responses
- Monoclonal and Polyclonal Antibodies Research
- Muscle Physiology and Disorders
- 3D Printing in Biomedical Research
- RNA Interference and Gene Delivery
- Genetic Syndromes and Imprinting
- Advanced biosensing and bioanalysis techniques
- Sarcoma Diagnosis and Treatment
- Epigenetics and DNA Methylation
- Cancer-related molecular mechanisms research
- Proteoglycans and glycosaminoglycans research
- Advanced Proteomics Techniques and Applications
The University of Texas Health Science Center at Houston
2010-2024
Brown Foundation
2012-2023
Baylor College of Medicine
2005-2010
Osaka University
1999
Saga University
1995-1999
Abstract The connection between obesity and accelerated cancer progression has been established, but the mediating mechanisms are not well understood. We have shown that stromal cells from white adipose tissue (WAT) cooperate with endothelium to promote blood vessel formation through secretion of soluble trophic factors. Here, we hypothesize WAT directly mediates by serving as a source migrate tumors neovascularization. To test this hypothesis, evaluated recruitment WAT-derived effect their...
Abstract Epidemiologic studies associate cancer with obesity, but the pathophysiologic connections remain obscure. In this study, we show that obesity facilitates tumor growth in mice irrespective of concurrent diet, suggesting a direct effect excess white adipose tissue (WAT). When transplanted into mice, stromal cells (ASC) can serve as perivascular adipocyte progenitors promote growth, perhaps helping explain obesity–cancer link. developing hypothesis, showed ASCs are expanded and they...
White adipose tissue (WAT) is becoming widely used in regenerative medicine/cell therapy applications, and its physiological pathological importance increasingly appreciated. WAT a complex organ composed of differentiated adipocytes, stromal mesenchymal progenitors known as cells (ASC), well endothelial vascular infiltrating leukocytes. Two-dimensional (2D) culture that has been typically for studying does not adequately recapitulate complexity. Improved methods reconstruction functional ex...
The relative abundance of thermogenic beige adipocytes and lipid-storing white in adipose tissue underlie its metabolic activity. roles adipocyte progenitor cells, which express PDGFRα or PDGFRβ, function have remained unclear. Here, by defining the developmental timing PDGFRβ expression mouse subcutaneous visceral depots, we uncover depot specificity pre-adipocyte delineation. We demonstrate that precedes all but only a fraction stromal cells. show high-fat diet feeding thermoneutrality...
The mechanism controlling long-chain fatty acid (LCFA) mobilization from adipose tissue is not well understood. Here, we investigated how the LCFA transporter CD36 regulates this process. By using tissue-specific KO mouse models, showed that in adipocytes and endothelial cells mediated both deposition into release tissue. We demonstrated role of adipocytic promoting tumor growth chemoresistance conferred by tissue–derived LCFAs. dynamic cysteine S-acylation adipocytes, cells, cancer...
Phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P(2)] is a key second messenger that regulates actin and membrane dynamics, as well other cellular processes. Many of the effects PtdIns(4,5)P(2) are mediated by binding to effector proteins contain pleckstrin homology (PH) domain. Here, we identify two novel effectors in budding yeast Saccharomyces cerevisiae: PH domain containing protein Slm1 its homolog Slm2. Slm2 serve redundant roles essential for cell growth cytoskeleton polarization....
We have previously identified prohibitin (PHB) and annexin A2 (ANX2) as proteins interacting on the surface of vascular endothelial cells in white adipose tissue (WAT) humans mice. Here, we demonstrate that ANX2 PHB also interact adipocytes. Mice lacking normal WAT vascularization, adipogenesis, glucose metabolism but display hypotrophy due to reduced fatty acid uptake by endothelium By using cell culture systems which ANX2/PHB binding is disrupted either genetically or through treatment...
Overgrowth of white adipose tissue (WAT) in obesity occurs as a result adipocyte hypertrophy and hyperplasia. Expansion renewal adipocytes relies on proliferation differentiation progenitors (WAP); however, the requirement WAP for development has not been proven. Here, we investigate whether depletion can be used to prevent WAT expansion. We test this approach by using hunter-killer peptide designed induce apoptosis selectively WAP. show that targeted cytoablation results long-term growth...
DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity excessive height. While known impact feeding behavior via the hypothalamus, here we investigated a role adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These become morbidly obese due enlargement tissue...
The PH domain-containing proteins Slm1 and Slm2 were previously identified as effectors of the phosphatidylinositol-4,5-bisphosphate (PI4,5P(2)) TORC2 signaling pathways. Here, we demonstrate that are also targets sphingolipid during heat shock response. We show upon depletion cellular levels, function becomes essential for survival under stress. further Slm regulated by a phosphorylation/dephosphorylation cycle involving sphingolipid-activated protein kinases Pkh1 Pkh2...
Cell migration requires the regulated disassembly of focal adhesions, but underlying mechanisms remain poorly defined. We have previously shown that adhesion dynamin 2- and clathrin-dependent endocytosis ligand-activated beta1 integrins. Here, we identify type I phosphatidylinositol phosphate kinase beta (PIPKIbeta), an enzyme generates phosphatidylinositol-4,5-bisphosphate (PI4,5P(2)), as a key regulator this process. found knockdown PIPKIbeta by RNA interference blocks internalization...
Progression of many cancers is associated with tumor infiltration by mesenchymal stromal cells (MSC). Adipose (ASC) are MSC that serve as adipocyte progenitors and endothelium-supporting in white adipose tissue (WAT). Clinical animal model studies indicate ASC mobilized from WAT recruited tumors. Direct evidence for function microenvironment has been lacking due to unavailability approaches specifically inactivate these cells. Here, we investigate the effects a proteolysis-resistant targeted...
<p>The effects of Pdgfrb+ CAF vs ASC-like depletion on the TME. A, tumor section immunofluorescence for CD3 (Red) expression to measure T-cell infiltration and nuclei (blue) (left), CD3+ cell quantification (right). B, endomucin (green) quantify endothelial density In A-B, each tumor, a minimum 15 fields (10X) were taken quantified using Image J. Images converted 8-bit threshold was applied only highlight percent area measured. An average calculated all images per tumor. Scale...
<p>The effects of <i>Pdgfrb</i>+ CAF vs. ASC-like depletion on the TME. Shown are representative analyses tumors from <a href="#fig1" target="_blank">Figs. 1</a> and href="#fig2" target="_blank">2</a>. <b>A,</b> t-distributed stochastic neighbor embedding clusters with cell populations identified based heatmap analysis (not shown) show changes in labeled populations. <b>B,</b> Changes frequencies cells corresponding to...
<div>Abstract<p>Immune checkpoint blockade therapy, transformative in some cancer types, has remained ineffective for patients with pancreatic cancer. The effects of subpopulations cancer-associated fibroblasts (CAF) on progression and therapy resistance are incompletely understood. In this study, the roles CAFs expressing platelet-derived growth factor receptor β (<i>Pdgfrb</i>) markers adipose stromal cells (ASC) were analyzed mice ductal adenocarcinoma. Ablation...
<p>A, Fig. 1 schematic of testing the effect Pdgfrb+ CAF depletion on PDAC progression. B, initial body weight in experiment A. C, A tumor section H&E staining showing inflammation (i), necrosis (n), and well-differentiated cells (arrows). D, Pdgfrb + pre-depletion E, D. F, weights G, 2 ASC-like H, G. I, G indicating (n) Scale Bars = 500μm. *=p<0.05.</p>
<p>ASC-like CAF depletion synergizes with immune checkpoint blockade. Following orthotopic grafting of KPC-Luc cells, female (<i>N</i> = 3 per group) and male mice received PBS, D-CAN, aPDL1, or the combination D-CAN + aPDL1. <b>A,</b> IVIS images two representative at day 22 showing location pancreatic primary tumor graft (arrow) extrapancreatic area invasion metastases (punctate). <b>B,</b> KPC size upon resection from females males....
<p>The effect of ASC-like CAF depletion on orthotopic PDAC progression. Tissues resected from male mice after 25 days D-CAN (<i>N</i> = 3) or control PBS treatment were analyzed. <b>A,</b> KPC tumor size upon resection. <b>B,</b> Representative tumors. <b>C,</b> Paraffin sections tumors in <b>B</b> stained with hematoxylin/eosin, trichrome blue, subjected to αSMA and endomucin immunofluorescence. Arrows indicate examples...
<p>The effect of <i>Pdgfrb</i>+ CAF depletion on orthotopic PDAC progression. Tissues resected from <i>Pdgfrb-TK</i> male mice after 25 days GCV (<i>N</i> = 3) or control PBS 4) treatment were analyzed. <b>A,</b> KPC tumor size upon resection. <b>B,</b> Representative tumors. <b>C,</b> Paraffin sections tumors in <b>B</b> stained with hematoxylin/eosin, trichrome blue, subjected to αSMA and endomucin...