Almost 100 years ago, Warburg described a metabolic change in energy flux during cancerous transformation. Since then, multiple studies have demonstrated how the anabolic synthesis of macromolecules can be altered to support cancer cell progression. Yet, the potential effect of altered catabolic degradation of macromolecules on tumor carcinogenesis has to be much more studied. We hypothesize that to support cancer growth robustly, catabolic pathways must be changed too. Thus, the focus of our studies was to identify changes in catabolism to improve cancer patients' diagnosis and therapy.
The urea cycle (UC) is mammals' main catabolic pathway to excrete waste nitrogen. Although the complete UC pathway is liver-specific, most tissues express different combinations of UC enzymes according to cellular needs. Encouragingly, we find that dysregulated expression of the UC pathway (UCD) is a global phenomenon in cancer that increases nitrogen availability for the synthesis of macromolecules by decreasing its urine excretion. This metabolic alteration is associated with poor patient prognosis. Thus, we hypothesize that UCD provides a significant metabolic advantage to multiple aspects of carcinogenesis and leads to specific, identifiable genomic and biochemical signatures, with implications for cancer diagnosis and therapy.
To pursue our hypothesis, we incorporated state-of-the-art comparative genomic, proteomic, metabolomic, and molecular approaches to explore this scientific "blind spot" of nitrogen catabolism in carcinogenesis. We investigated how UCD causally affects carcinogenesis by characterizing tumor-specific functions of UC enzymes (Aim I), correlating tumor phenotypes with systemic biomarkers (Aim II), and testing the treatment efficacy of drug combinations targeting UCD in cancers (Aim III).
We found that UCD advances carcinogenesis via promoting high nucleotide synthesis, especially of pyrimidines, generating a high pyrimidine-to-purine ratio (Nature 2015, Cell 2018). The consequent nucleotide imbalance induces a mutational signature that sensitizes the tumors to immunotherapy (Nature Cancer 2020). We further showed that we can metabolically induce a high pyrimidine-to-purine ratio to improve cancer response to immunotherapy.
Notably, we further demonstrated that the tumor metabolism changes affect the host and lead to systemic metabolic changes contributing to cachexia development (Cancer Discovery 2023). Hence, restoring liver metabolism can alleviate cachexia manifestations.
Our proposal, strengthened by my training as a physician-scientist, led to considerable potential for translational diagnostic and therapeutic impacts by identifying new diagnostic biomarkers for predicting and enhancing cancers' therapeutic response. Significantly, it added the host to the therapeutic equation. Indeed, I have been invited to contribute our insights from the changes in the urea cycle metabolism to alteration in the host systemic metabolism in multiple meetings and reviews in prestigious journals (Nature Review Cancer, Cell, Cancer Discovery, and more).
