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Raghu Kalluri

Thomas Brabletz, Raghu Kalluri, M Angela Nieto, Robert A Weinberg
Similar to embryonic development, changes in cell phenotypes defined as an epithelial to mesenchymal transition (EMT) have been shown to play a role in the tumorigenic process. Although the first description of EMT in cancer was in cell cultures, evidence for its role in vivo is now widely reported but also actively debated. Moreover, current research has exemplified just how complex this phenomenon is in cancer, leaving many exciting, open questions for researchers to answer in the future. With these points in mind, we asked four scientists for their opinions on the role of EMT in cancer and the challenges faced by scientists working in this fast-moving field...
January 12, 2018: Nature Reviews. Cancer
Jingjing Jiao, Álvaro González, Heather L Stevenson, Mihai Gagea, Hikaru Sugimoto, Raghu Kalluri, Laura Beretta
There is a pressing need for the development of novel approaches to treat and prevent hepatocellular carcinoma (HCC). The S100 calcium-binding protein S100A4 is associated with poor prognosis and metastasis in several human cancers. In addition, a role for S100A4 in modulating cancer-initiating cells stemness properties was recently proposed in head and neck and gastric cancers. Whether S100A4+ stromal cells contribute to tumor onset remains, however, an unanswered question. To address that question, we generated a new mouse model allowing for the depletion of S100A4+ cells in a mouse model of HCC with stemness properties, by crossing mice with hepatic deletion of phosphatase and tensin homolog (PTEN) with mice expressing viral thymidine kinase under the control of S100A4 promoter...
January 5, 2018: Experimental & Molecular Medicine
Javier Figueroa, Lynette M Phillips, Tal Shahar, Anwar Hossain, Joy Gumin, Hoon Kim, Andrew J Bean, George A Calin, Juan Fueyo, Edgar T Walters, Raghu Kalluri, Roel G Verhaak, Frederick F Lang
Tumor-stromal communications impact tumorigenesis in ways that are incompletely understood. Here, we show that glioma-associated human mesenchymal stem cells (GA-hMSC), a newly identified stromal component of glioblastoma, release exosomes that increase the proliferation and clonogenicity of tumor-initiating glioma stem-like cells (GSC). This event leads to a significantly greater tumor burden and decreased host survival compared with untreated GSCs in orthotopic xenografts. Analysis of the exosomal content identified miR-1587 as a mediator of the exosomal effects on GSCs, in part via downregulation of the tumor-suppressive nuclear receptor corepressor NCOR1...
November 1, 2017: Cancer Research
Michael W Pickup, Philip Owens, Agnieszka E Gorska, Anna Chytil, Fei Ye, Chanjuan Shi, Valerie M Weaver, Raghu Kalluri, Harold L Moses, Sergey V Novitskiy
The survival rate for pancreatic ductal adenocarcinoma (PDAC) remains low. More therapeutic options to treat this disease are needed, for the current standard of care is ineffective. Using an animal model of aggressive PDAC (Kras/p48(TGFβRIIKO)), we discovered an effect of TGFβ signaling in regulation of G-CSF secretion in pancreatic epithelium. Elevated concentrations of G-CSF in PDAC promoted differentiation of Ly6G(+) cells from progenitors, stimulated IL10 secretion from myeloid cells, and decreased T-cell proliferation via upregulation of Arg, iNOS, VEGF, IL6, and IL1b from CD11b(+) cells...
September 2017: Cancer Immunology Research
Sushrut Kamerkar, Valerie S LeBleu, Hikaru Sugimoto, Sujuan Yang, Carolina F Ruivo, Sonia A Melo, J Jack Lee, Raghu Kalluri
The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes are extracellular vesicles generated by all cells, and are naturally present in the blood. Here we show that enhanced retention of exosomes, compared to liposomes, in the circulation of mice is likely due to CD47-mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry short interfering RNA or short hairpin RNA specific to oncogenic KrasG12D , a common mutation in pancreatic cancer...
June 22, 2017: Nature
Paul Kurywchak, Raghu Kalluri
Chemotherapy is a predominant strategy to treat cancer and is often associated with toxicities like severe diarrhea that puts patients at additional risk and can hinder treatment strategies. Lian et al. recently explored the immune-mediated mechanisms of Irinotecan-induced diarrhea in colorectal cancer and found that double-stranded DNA in small vesicles can launch inflammation pathways in immune cells through the cytosolic DNA sensor AIM2.
June 2017: Cell Research
Julienne L Carstens, Pedro Correa de Sampaio, Dalu Yang, Souptik Barua, Huamin Wang, Arvind Rao, James P Allison, Valerie S LeBleu, Raghu Kalluri
The exact nature and dynamics of pancreatic ductal adenocarcinoma (PDAC) immune composition remains largely unknown. Desmoplasia is suggested to polarize PDAC immunity. Therefore, a comprehensive evaluation of the composition and distribution of desmoplastic elements and T-cell infiltration is necessary to delineate their roles. Here we develop a novel computational imaging technology for the simultaneous evaluation of eight distinct markers, allowing for spatial analysis of distinct populations within the same section...
April 27, 2017: Nature Communications
Raghu Kalluri, Valerie S LeBleu
It is becoming increasingly clear that small vesicles released from cells (extracellular vesicles [EVs]) represent a heterogeneous population implicated in cell-to-cell communication. The classifications and nomenclature of EVs are evolving as enrichment strategies and specific characteristics are being unraveled. At present, physical properties of EVs-namely, size, shape, and density-are often used to identify subpopulations of EVs. A distinct group of EVs, termed exosomes, largely defined by their small size (∼40-150 nm) and proposed subcellular origin, has been extensively studied in several aspects of cancer biology...
2016: Cold Spring Harbor Symposia on Quantitative Biology
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April 19, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Murad Megjhani, Pedro Correa de Sampaio, Julienne Leigh Carstens, Raghu Kalluri, Badrinath Roysam
Motivation: Current spectral unmixing methods for multiplex fluorescence microscopy have a limited ability to cope with high spectral overlap as they only analyze spectral information over individual pixels. Here, we present adaptive Morphologically Constrained Spectral Unmixing (MCSU) algorithms that overcome this limitation by exploiting morphological differences between sub-cellular structures, and their local spatial context. Results: The proposed method was effective at improving spectral unmixing performance by exploiting: (i) a set of dictionary-based models for object morphologies learned from the image data; and (ii) models of spatial context learned from the image data using a total variation algorithm...
July 15, 2017: Bioinformatics
Sujuan Yang, Sara P Y Che, Paul Kurywchak, Jena L Tavormina, Liv B Gansmo, Pedro Correa de Sampaio, Michael Tachezy, Maximilian Bockhorn, Florian Gebauer, Amanda R Haltom, Sonia A Melo, Valerie S LeBleu, Raghu Kalluri
Pancreatic cancer presents with a dismal mortality rate and is in urgent need of methods for early detection with potential for timely intervention. All living cells, including cancer cells, generate exosomes. We previously discovered double stranded genomic DNA in exosomes derived from the circulation of pancreatic cancer patients, which enabled the detection of prevalent mutations associated with the disease. Here, we report a proof-of-concept study that demonstrates the potential clinical utility of circulating exosomal DNA for identification of KRASG12D and TP53R273H mutations in patients with pancreas-associated pathologies, including pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP) and intraductal papillary mucinous neoplasm (IPMN), and in healthy human subjects...
March 4, 2017: Cancer Biology & Therapy
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...
January 2017: 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
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