Cancer metabolism View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2012-2015

FUNDING AMOUNT

1182595 GBP

ABSTRACT

Cancer remains one of the leading causes of death worldwide, despite significant advances in our understanding of its biology. Development of cancer therapeutics is challenging due, partly, to the vast diversity of the disease and underlying causes. A key attribute of successful cancer therapies is their ability to selectively target tumors while sparing healthy tissues. Therefore, identifying features that are common to a broad spectrum of cancers and distinguish them from normal cells is an important objective in cancer research. One such distinguishing feature of cancer cells is the way they use nutrients to survive and multiply, i.e. their metabolism. Our research aims at understanding how nutrient metabolism contributes to cancer development. Towards this goal, we are employing a multidisciplinary approach that includes metabolomics, biochemistry, microscopy, proteomics and mouse models, to elucidate the molecular mechanisms that distinguish the metabolism of tumors from that of normal tissues. A further aim of our work is to define principles for rational targeting of cancer metabolism as a therapeutic strategy. Technical Summary Cancer cells utilise nutrients in a distinct manner compared to most normal cells. This phenomenon reflects, in part, an increased demand for cellular building blocks to support proliferation, as well as a need to deal with the unique challenges that cancer cells face from their environment. One aspect of our recent work has focused on the glycolytic enzyme PKM2. We showed that PKM2 helps cancer cells survive under oxidative stress elicited by low oxygen concentrations (hypoxia), a condition often encountered in tumours, by altering the way they metabolize glucose. Small molecule activators of PKM2 disrupt this process to impede proliferation and sensitize cancers to oxidant-induced death. Our results indicate that activation of PKM2 could be a useful therapeutic approach for a broad spectrum of cancers and suggest clinical settings where PKM2 activators could be effectively combined with existing drugs to improve their therapeutic potential. Our lab currently continues to investigate the molecular mechanisms that underlie the characteristic metabolism of tumours using biochemical and metabolomics approaches. A major theme focuses on identifying alternative carbon sources (i.e. carbon sources other than glucose and glutamine, which are known to be heavily used by cancer cells) that fuel anabolic processes or are required for other aspects of cancer development. We are further interested in understanding how the metabolic features of individual cell types within the tumour niche influence cancer development. Towards this goal, we are developing advanced mouse cancer models that permit genetic manipulation of metabolic enzyme activities in individual cell types found within the tumour microenvironment. These studies are complemented by structure-based design of molecular biosensors to probe metabolism in vivo, at the single-cell level. More... »

URL

http://gtr.rcuk.ac.uk/project/E0E62A79-6F19-44D1-8521-AF3BA69AFF28

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