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Raghu Kalluri

Björn Tampe, Ulrike Steinle, Désirée Tampe, Julienne L Carstens, Peter Korsten, Elisabeth M Zeisberg, Gerhard A Müller, Raghu Kalluri, Michael Zeisberg
Acute kidney injury (AKI) and progressive chronic kidney disease (CKD) are intrinsically tied syndromes. In this regard, the acutely injured kidney often does not achieve its full regenerative capacity and AKI directly transitions into progressive CKD associated with tubulointerstitial fibrosis. Underlying mechanisms of such AKI-to-CKD progression are still incompletely understood and specific therapeutic interventions are still elusive. Because epigenetic modifications play a role in maintaining tissue fibrosis, we used a murine model of ischemia-reperfusion injury to determine whether aberrant promoter methylation of RASAL1 contributes causally to the switch between physiological regeneration and tubulointerstitial fibrogenesis, a hallmark of AKI-to-CKD progression...
September 27, 2016: Kidney International
Raghu Kalluri
Among all cells, fibroblasts could be considered the cockroaches of the human body. They survive severe stress that is usually lethal to all other cells, and they are the only normal cell type that can be live-cultured from post-mortem and decaying tissue. Their resilient adaptation may reside in their intrinsic survival programmes and cellular plasticity. Cancer is associated with fibroblasts at all stages of disease progression, including metastasis, and they are a considerable component of the general host response to tissue damage caused by cancer cells...
August 23, 2016: Nature Reviews. Cancer
Sara Lovisa, Michael Zeisberg, Raghu Kalluri
Kidney fibrosis is the unavoidable consequence of chronic kidney disease irrespective of the primary underlying insult. It is a complex phenomenon governed by the interplay between different cellular components and intricate networks of signaling pathways, which together lead to loss of renal functionality and replacement of kidney parenchyma with scar tissue. An immense effort has recently been made to understand the molecular and cellular mechanisms leading to kidney fibrosis. The cellular protagonists of this process include myofibroblasts, tubular epithelial cells, endothelial cells, and immune cells...
October 2016: Trends in Endocrinology and Metabolism: TEM
Hanane Laklai, Yekaterina A Miroshnikova, Michael W Pickup, Eric A Collisson, Grace E Kim, Alex S Barrett, Ryan C Hill, Johnathon N Lakins, David D Schlaepfer, Janna K Mouw, Valerie S LeBleu, Nilotpal Roy, Sergey V Novitskiy, Julia S Johansen, Valeria Poli, Raghu Kalluri, Christine A Iacobuzio-Donahue, Laura D Wood, Matthias Hebrok, Kirk Hansen, Harold L Moses, Valerie M Weaver
Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension...
May 2016: Nature Medicine
Raghu Kalluri
Humans circulate quadrillions of exosomes at all times. Exosomes are a class of extracellular vesicles released by all cells, with a size range of 40-150 nm and a lipid bilayer membrane. Exosomes contain DNA, RNA, and proteins. Exosomes likely remove excess and/or unnecessary constituents from the cells, functioning like garbage bags, although their precise physiological role remains unknown. Additionally, exosomes may mediate specific cell-to-cell communication and activate signaling pathways in cells they fuse or interact with...
April 1, 2016: Journal of Clinical Investigation
Timothy P Cleland, Elena R Schroeter, Leonid Zamdborg, Wenxia Zheng, Ji Eun Lee, John C Tran, Marshall Bern, Michael B Duncan, Valerie S Lebleu, Dorothy R Ahlf, Paul M Thomas, Raghu Kalluri, Neil L Kelleher, Mary H Schweitzer
Structures similar to blood vessels in location, morphology, flexibility, and transparency have been recovered after demineralization of multiple dinosaur cortical bone fragments from multiple specimens, some of which are as old as 80 Ma. These structures were hypothesized to be either endogenous to the bone (i.e., of vascular origin) or the result of biofilm colonizing the empty osteonal network after degradation of original organic components. Here, we test the hypothesis that these structures are endogenous and thus retain proteins in common with extant archosaur blood vessels that can be detected with high-resolution mass spectrometry and confirmed by immunofluorescence...
December 4, 2015: Journal of Proteome Research
Xiaofeng Zheng, Julienne L Carstens, Jiha Kim, Matthew Scheible, Judith Kaye, Hikaru Sugimoto, Chia-Chin Wu, Valerie S LeBleu, Raghu Kalluri
Diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis despite current best therapies; therefore new treatment strategies are urgently required. Numerous studies have suggested that epithelial-to-mesenchymal transition (EMT) contributes to early-stage dissemination of cancer cells and is pivotal for invasion and metastasis of PDAC. EMT is associated with phenotypic conversion of epithelial cells into mesenchymal-like cells in cell culture conditions, although such defined mesenchymal conversion (with spindle-shaped morphology) of epithelial cells in vivo is rare, with quasi-mesenchymal phenotypes occasionally observed in the tumour (partial EMT)...
November 26, 2015: Nature
Sara Lovisa, Valerie S LeBleu, Björn Tampe, Hikaru Sugimoto, Komal Vadnagara, Julienne L Carstens, Chia-Chin Wu, Yohannes Hagos, Birgitta C Burckhardt, Tsvetelina Pentcheva-Hoang, Hersharan Nischal, James P Allison, Michael Zeisberg, Raghu Kalluri
Kidney fibrosis is marked by an epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs). Here we find that, during renal fibrosis, TECs acquire a partial EMT program during which they remain associated with their basement membrane and express markers of both epithelial and mesenchymal cells. The functional consequence of the EMT program during fibrotic injury is an arrest in the G2 phase of the cell cycle and lower expression of several solute and solvent transporters in TECs. We also found that transgenic expression of either Twist1 (encoding twist family bHLH transcription factor 1, known as Twist) or Snai1 (encoding snail family zinc finger 1, known as Snail) expression is sufficient to promote prolonged TGF-β1-induced G2 arrest of TECs, limiting the cells' potential for repair and regeneration...
September 2015: Nature Medicine
Sonia A Melo, Linda B Luecke, Christoph Kahlert, Agustin F Fernandez, Seth T Gammon, Judith Kaye, Valerie S LeBleu, Elizabeth A Mittendorf, Juergen Weitz, Nuh Rahbari, Christoph Reissfelder, Christian Pilarsky, Mario F Fraga, David Piwnica-Worms, Raghu Kalluri
Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cell-derived exosomes. GPC1(+) circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer...
July 9, 2015: Nature
Nicolas Léveillé, Carlos A Melo, Koos Rooijers, Angel Díaz-Lagares, Sonia A Melo, Gozde Korkmaz, Rui Lopes, Farhad Akbari Moqadam, Ana R Maia, Patrick J Wijchers, Geert Geeven, Monique L den Boer, Raghu Kalluri, Wouter de Laat, Manel Esteller, Reuven Agami
p53 binds enhancers to regulate key target genes. Here, we globally mapped p53-regulated enhancers by looking at enhancer RNA (eRNA) production. Intriguingly, while many p53-induced enhancers contained p53-binding sites, most did not. As long non-coding RNAs (lncRNAs) are prominent regulators of chromatin dynamics, we hypothesized that p53-induced lncRNAs contribute to the activation of enhancers by p53. Among p53-induced lncRNAs, we identified LED and demonstrate that its suppression attenuates p53 function...
2015: Nature Communications
Michael Zeisberg, Raghu Kalluri
Long overlooked as the virtual compartment and then strictly characterized through descriptive morphologic analysis, the renal interstitium has finally been associated with function. With identification of interstitial renin- and erythropoietin-producing cells, the most prominent endocrine functions of the kidney have now been attributed to the renal interstitium. This article reviews the functional role of renal interstitium.
October 7, 2015: Clinical Journal of the American Society of Nephrology: CJASN
Jing Zhang, Jingjing Jiao, Silvia Cermelli, Kyle Muir, Kwang Hwa Jung, Ruhai Zou, Asif Rashid, Mihai Gagea, Sonya Zabludoff, Raghu Kalluri, Laura Beretta
miR-21 is upregulated in hepatocellular carcinoma and intrahepatic cholangiocarcinoma, where it is associated with poor prognosis. Here, we offer preclinical evidence that miR-21 offers a therapeutic and chemopreventive target in these liver cancers. In mice with hepatic deletion of Pten, anti-miR-21 treatment reduced liver tumor growth and prevented tumor development. These effects were accompanied with a decrease in liver fibrosis and a concomitant reduction of CD24(+) liver progenitor cells and S100A4(+) cancer-associated stromal cells...
May 1, 2015: Cancer Research
Björn Tampe, Desiree Tampe, Elisabeth M Zeisberg, Gerhard A Müller, Wibke Bechtel-Walz, Michael Koziolek, Raghu Kalluri, Michael Zeisberg
Progression of chronic kidney disease remains a principal problem in clinical nephrology and there is a pressing need for novel therapeutics and biomarkers. Aberrant promoter CpG island methylation and subsequent transcriptional silencing of specific genes have emerged as contributors to progression of chronic kidney disease. Here, we report that transcriptional silencing of the Ras-GTP suppressor RASAL1 contributes causally to progression of kidney fibrosis and we identified that circulating methylated RASAL1 promoter DNA fragments in peripheral blood correspond with levels of intrarenal levels of RASAL1 promoter methylation and degree of fibrosis in kidney biopsies, enabling non-invasive longitudinal analysis of intrarenal CpG island methylation...
January 2015: EBioMedicine
Doruk Keskin, Jiha Kim, Vesselina G Cooke, Chia-Chin Wu, Hikaru Sugimoto, Chenghua Gu, Michele De Palma, Raghu Kalluri, Valerie S LeBleu
Strategies to target angiogenesis include inhibition of the vessel-stabilizing properties of vascular pericytes. Pericyte depletion in early-stage non-hypoxic tumors suppressed nascent angiogenesis, tumor growth, and lung metastasis. In contrast, pericyte depletion in advanced-stage hypoxic tumors with pre-established vasculature resulted in enhanced intra-tumoral hypoxia, decreased tumor growth, and increased lung metastasis. Furthermore, depletion of pericytes in post-natal retinal blood vessels resulted in abnormal and leaky vasculature...
February 24, 2015: Cell Reports
Xingbo Xu, Xiaoying Tan, Björn Tampe, Gunsmaa Nyamsuren, Xiaopeng Liu, Lars S Maier, Samuel Sossalla, Raghu Kalluri, Michael Zeisberg, Gerd Hasenfuss, Elisabeth M Zeisberg
AIMS: Methylation of CpG island promoters is a prototypical epigenetic mechanism to stably control gene expression. The aim of this study was to elucidate the contribution of aberrant promoter DNA methylation in pathological endothelial to mesenchymal transition (EndMT) and subsequent cardiac fibrosis. METHODS AND RESULTS: In human coronary endothelial cells, TGFβ1 causes aberrant methylation of RASAL1 promoter, increased Ras-GTP activity, and EndMT. In end-stage failing vs...
March 1, 2015: Cardiovascular Research
Xingbo Xu, Ingeborg Friehs, Tachi Zhong Hu, Ivan Melnychenko, Björn Tampe, Fouzi Alnour, Maria Iascone, Raghu Kalluri, Michael Zeisberg, Pedro J Del Nido, Elisabeth M Zeisberg
RATIONALE: Endocardial fibroelastosis (EFE) is a unique form of fibrosis, which forms a de novo subendocardial tissue layer encapsulating the myocardium and stunting its growth, and which is typically associated with congenital heart diseases of heterogeneous origin, such as hypoplastic left heart syndrome. Relevance of EFE was only recently highlighted through the establishment of staged biventricular repair surgery in infant patients with hypoplastic left heart syndrome, where surgical removal of EFE tissue has resulted in improvement in the restrictive physiology leading to the growth of the left ventricle in parallel with somatic growth...
February 27, 2015: Circulation Research
Sonia A Melo, Hikaru Sugimoto, Joyce T O'Connell, Noritoshi Kato, Alberto Villanueva, August Vidal, Le Qiu, Edward Vitkin, Lev T Perelman, Carlos A Melo, Anthony Lucci, Cristina Ivan, George A Calin, Raghu Kalluri
Exosomes are secreted by all cell types and contain proteins and nucleic acids. Here, we report that breast cancer associated exosomes contain microRNAs (miRNAs) associated with the RISC-Loading Complex (RLC) and display cell-independent capacity to process precursor microRNAs (pre-miRNAs) into mature miRNAs. Pre-miRNAs, along with Dicer, AGO2, and TRBP, are present in exosomes of cancer cells. CD43 mediates the accumulation of Dicer specifically in cancer exosomes. Cancer exosomes mediate an efficient and rapid silencing of mRNAs to reprogram the target cell transcriptome...
November 10, 2014: Cancer Cell
Toru Miyake, Raghu Kalluri
No abstract text is available yet for this article.
October 30, 2014: Nature
Valerie S LeBleu, Joyce T O'Connell, Karina N Gonzalez Herrera, Harriet Wikman, Klaus Pantel, Marcia C Haigis, Fernanda Machado de Carvalho, Aline Damascena, Ludmilla Thome Domingos Chinen, Rafael M Rocha, John M Asara, Raghu Kalluri
Cancer cells can divert metabolites into anabolic pathways to support their rapid proliferation and to accumulate the cellular building blocks required for tumour growth. However, the specific bioenergetic profile of invasive and metastatic cancer cells is unknown. Here we report that migratory/invasive cancer cells specifically favour mitochondrial respiration and increased ATP production. Invasive cancer cells use the transcription coactivator peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A, also known as PGC-1α) to enhance oxidative phosphorylation, mitochondrial biogenesis and the oxygen consumption rate...
October 2014: Nature Cell Biology
Michael Zeisberg, Björn Tampe, Valerie LeBleu, Desiree Tampe, Elisabeth M Zeisberg, Raghu Kalluri
Thrombospondin-1 (TSP1) is a multifunctional matricellular protein known to promote progression of chronic kidney disease. To gain insight into the underlying mechanisms through which TSP1 accelerates chronic kidney disease, we compared disease progression in Col4a3 knockout (KO) mice, which develop spontaneous kidney failure, with that of Col4a3;Tsp1 double-knockout (DKO) mice. Decline of excretory renal function was significantly delayed in the absence of TSP1. Although Col4a3;Tsp1 DKO mice did progress toward end-stage renal failure, their kidneys exhibited distinct histopathological lesions, compared with creatinine level-matched Col4a3 KO mice...
October 2014: American Journal of Pathology
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