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Deciphering the metabolic roles of the urea-cycle pathway in carcinogenesis for improving diagnosis and therapy

Project description

Alterations in the urea cycle in cancer

It is well established that cancer cells alter their anabolic profile to accommodate their enhanced metabolic needs for proliferation and progression. The EU-funded UreaCa project is focussing on cancer cell catabolism, and in particular the urea cycle (UC), which is responsible for nitrogen excretion. Scientists will investigate the hypothesis that cancer cells excrete less nitrogen to promote macromolecule synthesis. Through state-of-the-art omics approaches, they will study UC enzymes and associate them with particular cancer phenotypes. Results will elucidate the implication of the UC pathway in carcinogenesis and unveil novel therapeutic avenues for cancer.


Almost 100 years ago, Warburg described a metabolic change in energy flux that occurs during carcinogenesis. Since then, multiple studies have demonstrated how anabolic synthesis of macromolecules can be altered to support cancer cell progression. Yet, the potential effect of altered catabolic degradation of macromolecules on tumour carcinogenesis has been much less studied.

The urea cycle (UC) is the main catabolic pathway by which mammals excrete waste nitrogen. Although the complete UC pathway is liver-specific, most tissues express different combinations of UC enzymes according to the cellular needs. Surprisingly, we find that changes in expression of UC components causing UC dysregulation, (UCD) is a global phenomenon in cancer, metabolically augmenting net nitrogen usage for the synthesis of macromolecules by reducing nitrogen waste. This metabolic alteration is associated with poor patient prognosis. Thus, we hypothesise that UCD provides a major metabolic advantage to multiple aspects of carcinogenesis and as such, leads to specific, identifiable genomic and biochemical signatures, with implications for cancer diagnosis and therapy.

To pursue our hypothesis, we will incorporate state-of-the-art comparative genomic, peptidomic, metabolomic, and molecular approaches to explore this scientific “blind spot” of nitrogen metabolism in carcinogenesis. We will investigate how UCD causally affects carcinogenesis, by characterising tumour-specific functions of UC enzymes (Aim I), correlating tumour phenotypes with systemic biomarkers (Aim II), and testing the treatment efficacy of drug combinations targeting UCD in cancers (Aim III).

Our proposal, strengthened by my training as a physician scientist, harbours considerable potential for translational diagnostic and therapeutic utility of our findings, enabling us to i) identify new diagnostic biomarkers for monitoring cancer initiation and progression and ii) predict and enhance the therapeutic response.


Net EU contribution
€ 2 000 000,00
Herzl street 234
7610001 Rehovot

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Activity type
Higher or Secondary Education Establishments
Other funding
€ 0,00

Beneficiaries (1)