Showing papers by "Raghu Kalluri published in 2014"

PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis

Abstract: Kalluri and colleagues find that mitochondrial biogenesis and respiration induced by transcriptional coactivator PGC-1α in cancer cells promote cancer metastasis and that PGC-1α expression is associated with invasive breast cancer.

Erratum: PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis (Nature Cell Biology (2014) 16 (992-1003))

Abstract: Corrigendum: PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis

Tet3-Mediated Hydroxymethylation of Epigenetically Silenced Genes Contributes to Bone Morphogenic Protein 7-Induced Reversal of Kidney Fibrosis

Abstract: Methylation of CpG island promoters is an epigenetic event that can effectively silence transcription over multiple cell generations. Hypermethylation of the Rasal1 promoter contributes to activation of fibroblasts and progression of kidney fibrosis. Here, we explored whether such causative hypermethylation could be reversed through endogenous mechanisms and whether such reversal of hypermethylation is a constituent of the antifibrotic activity of bone morphogenic protein 7 (BMP7). We show that successful inhibition of experimental kidney fibrosis through administration of BMP7 associates with normalization of Rasal1 promoter hypermethylation. Furthermore, this reversal of pathologic hypermethylation was achieved specifically through Tet3-mediated hydroxymethylation. Collectively, our findings reveal a new mechanism that may be exploited to facilitate therapeutic DNA demethylation to reverse kidney fibrosis.

Microenvironment-dependent cues trigger miRNA-regulated feedback loop to facilitate the EMT/MET switch.

Abstract: The metastatic spread of tumor epithelial cells accounts for over 90% of cancer-specific mortality; however, the molecular mechanisms that govern tumor spread and distant recolonization remain unclear. In this issue of JCI, Rokavec and colleagues shine light on this murky aspect of tumor biology by focusing through the lens of microenvironmental contributions, namely inflammation, as driving signals that set off a delicate, intracellular feedback loop among cytokine receptors, transcription factors and miRNAs. This study provides in vivo evidence and identifies molecular players behind the elusive switch that drives the epithelial-to-mesenchymal transition and the mesenchymal-to-epithelial transition.

Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure.

Abstract: 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. Although kidneys of both Col4a3 KO and Col4a3;Tsp1 DKO mice exhibited a widened tubulointerstitium, predominant lesions in Col4a3 KO kidneys were collagen deposition and fibroblast accumulation, whereas in Col4a3;Tsp1 DKO kidney inflammation was predominant, with less collagen deposition. Altered disease progression correlated with impaired activation of transforming growth factor-β1 (TGF-β1) in vivo and in vitro in the absence of TSP1. In summary, our findings suggest that TSP1 contributes to progression of chronic kidney disease by catalyzing activation of latent TGF-β1, resulting in promotion of a fibroproliferative response over an inflammatory response. Furthermore, the findings suggest that fibroproliferative and inflammatory lesions are independent entities, both of which contribute to decline of renal function.

Analysis of genomic dna, rna, and proteins in exosomes for diagnosis and theranosis

Abstract: The present invention provides that exosomes from human body fluid samples contain double stranded genomic DNA that spans all chromosomes and may be used to determine the mutation status of genes of interest in diseases, such as cancer. Furthermore, the present invention provides the use of exosomes to produce therapeutic proteins and for their use in therapy as well as the detection of cancer cell-derived exosomes to diagnose cancer and monitor therapeutic response.

Mirna biogenesis in exosomes for diagnosis and therapy

Abstract: Methods for diagnosis and treatment of cancers by use of exosomes comprsing miRNAs and precursors thereof For example, in some aspects, a cancer may be diagnosed or evaluated by determining the miRNA content of exosomes in a sample from a subject or by detecting miRNA processing in exosomes

Cardiac biology: Cell plasticity helps hearts to repair

Abstract: Fibroblast cells are known as key players in the repair of damaged heart structures. New findings show that injury also induces fibroblasts to become endothelial cells, helping to mend damaged blood vessels. See Article p.585 Cardiac fibroblasts are thought to be terminally differentiated cells. Arjun Deb and colleagues now show that cardiac injury prompts these fibroblasts to undergo mesenchymal–endothelial transition (MEndoT) and acquire endothelial-cell-like fate, a process mediated, in part, via a p53-dependent mechanism. They find that decreasing MEndoT by p53 deletion leads to reduced vascular density after ischaemic injury and worsened heart function. Conversely, use of a small-molecule activator of p53 increases MEndoT, leading to better preservation of heart function and reduced scarring.

Specific activation of K-RasG12D allele in the bladder urothelium results in lung alveolar and vascular defects.

Abstract: K-ras is essential for embryogenesis and its mutations are involved in human developmental syndromes and cancer. To determine the consequences of K-ras activation in urothelium, we used uroplakin-II (UPK II) promoter driven Cre recombinase mice and generated mice with mutated KrasG12D allele in the urothelium (UPK II-Cre;LSL-K-rasG12D). The UPK II-Cre;LSL-K-rasG12D mice died neonatally due to lung morphogenesis defects consisting of simplification with enlargement of terminal air spaces and dysmorphic pulmonary vasculature. A significant alteration in epithelial and vascular basement membranes, together with fragmentation of laminin, points to extracellular matrix degradation as the causative mechanism of alveolar and vascular defects. Our data also suggest that altered protease activity in amniotic fluid might be associated with matrix defects in lung of UPK II-Cre;LSL-K-rasG12. These defects resemble those observed in early stage human neonatal bronchopulmonary dysplasia (BPD), although the relevance of this new mouse model for BPD study needs further investigation.

Methods and compositions for human epididymis protein-4 (he4)

Abstract: The present invention relates to methods, compositions, and diagnostic tests for treating and diagnosing a subject with organ fibrosis or a risk of developing organ fibrosis. The present invention also relates to methods and compositions for treating a subject with a proliferative disease. In particular, the methods and compositions include treatment of organ fibrosis or a proliferative disease using an inhibitor of human epididymis protein-4 (HE4).