Skip to main content
European Commission logo
français français
CORDIS - Résultats de la recherche de l’UE
CORDIS
CORDIS Web 30th anniversary CORDIS Web 30th anniversary

Surviving metabolism: acid handling and signalling

Objectif

Metabolism generates vast quantities of acid, which exerts broad-spectrum biological effects because protein protonation is a powerful post-translational modification. Regulation of intracellular pH (pHi) is therefore a homeostatic priority, but carefully orchestrated proton dynamics are a versatile signal.
Extracellular acidity is an established chemical signature of tumours and has recently been proposed to convey a signal that shapes the phenotypic landscape of cancer. Cancers genetic instability yields diversity in acid handling and signalling, forming a substrate for selection under acid-stress. This is a plausible mechanism for disease progression and an analogy can be drawn to experimentally-verified hypoxic selection.
Current models of acid handling in cancer are, however, based on population-averages of observations made at the cell level. This fails to appreciate diversity and the complexity inherent in tissues. We will produce a more complete understanding of acid handling that accounts for diffusive transport across tissue compartments and the role of the tumour stroma. A systems-approach of characterising pH-regulatory processes cell-by-cell will identify which components are liable to vary, and thus are a substrate for acid-driven somatic evolution.
The long-term effects of proton signals on gene expression have not been tested, despite evidence for proton-sensing transcription factors. To address the mechanism for adaptation to acid-stress, proton-sensing transcription factors will be characterised from studies of gene expression under chemically and optogenetically operated pH stimuli.
The definition of a cells fitness to survive at a particular microenvironment pH and its relationship with stemness remain unclear. Phenotyping pHi-gated subpopulations in terms of growth, stemness and tumourigenicity will define pH-fitness and its role in aggressiveness. In evolving to survive metabolism, cancer cells may acquire the ability to thrive in new niches.

Champ scientifique (EuroSciVoc)

CORDIS classe les projets avec EuroSciVoc, une taxonomie multilingue des domaines scientifiques, grâce à un processus semi-automatique basé sur des techniques TLN.

Vous devez vous identifier ou vous inscrire pour utiliser cette fonction

Régime de financement

ERC-COG - Consolidator Grant

Institution d’accueil

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Contribution nette de l'UE
€ 1 922 575,00
Adresse
WELLINGTON SQUARE UNIVERSITY OFFICES
OX1 2JD Oxford
Royaume-Uni

Voir sur la carte

Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
€ 1 922 575,00

Bénéficiaires (1)