Periodic Reporting for period 4 - UreaCa (Deciphering the metabolic roles of the urea-cycle pathway in carcinogenesis for improving diagnosis and therapy)
Okres sprawozdawczy: 2023-11-01 do 2024-04-30
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).
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).
During the time that has passed since the beginning of this project, we have identified a way to predict patients' response to immunotherapy and improve the response to immunotherapy in unresponsive patients (Cell 2018, Nature Cancer 2020).
Along the way, we demonstrated a specific rewiring in cancer that channels amino acid to nucleotide synthesis rather than disposal, specifically increasing pyrimidine nucleotides (Nature 2015). We showed that the rise in pyrimidine levels generates a nucleotide imbalance that induces a unique mutational signature, which can predict response to immunotherapy (Cell 2018). Furthermore, these genomic changes lead to the presentation of more immunogenic neo-antigens, which augment cancer response to immunotherapy.
In our recent work, we took this finding a step further and showed that increasing pyrimidine levels converts tumors documented to be unresponsive to immunotherapy into responsive ones in both cancer mouse models and human patients. This exciting result led to a patent development and 3 invited reviews in impactful journals (Cancer Discovery, Molecular Cell, and Science Advances). Yet, this approach has a caveat as it involves decreasing purine levels using Mizoribine, causing immunosuppression, and hence, requiring a step-wise approach. We are now continuously looking for ways to metabolically induce high pyrimidine levels without perturbing purine synthesis.
Incidentally, while evaluating the changes in nucleotide metabolism following UCD, we identified a moonlighting nuclear function for ASS1, a cytosolic enzyme. These results were published in Mature Medicine as they have therapeutic implications for cancer patients with mutations in DNA repair genes and for patients with citrullinemia who have germline mutations in ASS1.
Finally, in more recent work published in Cancer Discovery 2023, we demonstrate that liver metabolism is affected by extrahepatic cancers leading to systemic changes and promoting cancer progression to cachexia. Notably, maintaining liver metabolism restricts cancer growth and alleviates cachexia symptoms. These results are highly impactful as they emphasize the importance of the tumor MACRO-environment, meaning the host, when treating cancer patients. To disseminate this concept, I presented our work in prestigious meetings, and contributed to a review published in Cell for its 50th anniversary, highlighting the changes in the host metabolism as a hallmark of cancer.
Along the way, we demonstrated a specific rewiring in cancer that channels amino acid to nucleotide synthesis rather than disposal, specifically increasing pyrimidine nucleotides (Nature 2015). We showed that the rise in pyrimidine levels generates a nucleotide imbalance that induces a unique mutational signature, which can predict response to immunotherapy (Cell 2018). Furthermore, these genomic changes lead to the presentation of more immunogenic neo-antigens, which augment cancer response to immunotherapy.
In our recent work, we took this finding a step further and showed that increasing pyrimidine levels converts tumors documented to be unresponsive to immunotherapy into responsive ones in both cancer mouse models and human patients. This exciting result led to a patent development and 3 invited reviews in impactful journals (Cancer Discovery, Molecular Cell, and Science Advances). Yet, this approach has a caveat as it involves decreasing purine levels using Mizoribine, causing immunosuppression, and hence, requiring a step-wise approach. We are now continuously looking for ways to metabolically induce high pyrimidine levels without perturbing purine synthesis.
Incidentally, while evaluating the changes in nucleotide metabolism following UCD, we identified a moonlighting nuclear function for ASS1, a cytosolic enzyme. These results were published in Mature Medicine as they have therapeutic implications for cancer patients with mutations in DNA repair genes and for patients with citrullinemia who have germline mutations in ASS1.
Finally, in more recent work published in Cancer Discovery 2023, we demonstrate that liver metabolism is affected by extrahepatic cancers leading to systemic changes and promoting cancer progression to cachexia. Notably, maintaining liver metabolism restricts cancer growth and alleviates cachexia symptoms. These results are highly impactful as they emphasize the importance of the tumor MACRO-environment, meaning the host, when treating cancer patients. To disseminate this concept, I presented our work in prestigious meetings, and contributed to a review published in Cell for its 50th anniversary, highlighting the changes in the host metabolism as a hallmark of cancer.
While focusing on the changes in cancer metabolism during tumorigenesis, we noticed significant changes occurring in the systemic metabolism of the host. Importantly, we found that we can preserve liver metabolism during carcinogenesis by re-expression of the liver master metabolic regulator Hepatic Nuclear Factor 4 (HNF4a). Furthermore, re-expressing HNF4a restricted tumor growth and the development of cachexia manifestations. Thus, this unexpected result potentially holds substantial implications for cancer diagnosis and therapy. Indeed, our results, supported by ERC-PoC, led to a patent and the establishment of a new company- Metabocure, which will evaluate the potential benefit of mRNA of HNF4a delivered via lipid nanoparticles (LNPs) in alleviating cancer cachexia in mice and human.