Dataset Information

The Francis Crick Institute

ABSTRACT: Organisation EGAO00000000464

PROVIDER: EGAO00000000464 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Publications

Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

de Bruin Elza C EC McGranahan Nicholas N Mitter Richard R Salm Max M Wedge David C DC Yates Lucy L Jamal-Hanjani Mariam M Shafi Seema S Murugaesu Nirupa N Rowan Andrew J AJ Grönroos Eva E Muhammad Madiha A MA Horswell Stuart S Gerlinger Marco M Varela Ignacio I Jones David D Marshall John J Voet Thierry T Van Loo Peter P Rassl Doris M DM Rintoul Robert C RC Janes Sam M SM Lee Siow-Ming SM Forster Martin M Ahmad Tanya T Lawrence David D Falzon Mary M Capitanio Arrigo A Harkins Timothy T TT Lee Clarence C CC Tom Warren W Teefe Enock E Chen Shann-Ching SC Begum Sharmin S Rabinowitz Adam A Phillimore Benjamin B Spencer-Dene Bradley B Stamp Gordon G Szallasi Zoltan Z Matthews Nik N Stewart Aengus A Campbell Peter P Swanton Charles C

Science (New York, N.Y.) 20141001 6206

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cy ...[more]

PMID: 25301630

Publication: 1/2

Similar Datasets

Project description:Neural control of visceral organ function is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence and is often dysregulated in gastrointestinal (GI) disorders. Luminal factors, such as diet and microbiota regulate neurogenic programs of gut motility, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor Aryl hydrocarbon Receptor (AhR) functions as a biosensor in intestinal neural circuits linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons representing distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles controlled by the combined effects of host genetic programmes and microbial colonisation. Microbiota-induced expression of AhR in neurons of the distal gastrointestinal tract enables them to respond to the luminal environment and induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in enteric neurons of antibiotic-treated mice partially restores intestinal motility. Taken together, our experiments identify AhR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits towards gut homeostasis and health. The enteric nervous system (ENS) encompasses the intrinsic neural networks of the gastrointestinal (GI) tract, which regulate most aspects of intestinal physiology, including peristalsis. In addition to host-specific genetic programmes, microbiota and diet have emerged as critical regulators of gut tissue physiology and changes in the microbial composition of the lumen often accompany GI disorders. However the molecular mechanisms by which gut enviromental factors regulate ENS homeostasis remain unknown. In order to address this issue, we used RNA sequencing to identify genes specifically upregulated in mouse colonic neurons in response to microbial colonisation.

Dataset Information

The Francis Crick Institute

Publications

Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets