Mapping how metabolism rewires protein function in cancer
All cells metabolize nutrients to generate the energy and molecular building blocks required for survival. Cancer cells, however, do it differently. To sustain rapid growth and adapt to hostile environments, they extensively rewire their metabolic machinery. Recent studies suggest that metabolism plays a much broader role than simply meeting the bioenergetic and biosynthetic demands of the cell,…
Recent scientific studies have unveiled the extent to which cancer cells alter their metabolic pathways to support rapid growth and adaptability in challenging environments. While the role of metabolism in powering cells is well-established, it is now recognized that metabolites play a pivotal role in regulating protein function and signaling within cells.
However, the mechanisms by which these metabolic shifts directly impact protein functionality and dictate cellular behavior remain largely unexplored. Two leading researchers at The Rockefeller University, Ekaterina V. Vinogradova and Kivanç Birsoy, have united their expertise in cancer metabolism, organelle biology, chemical proteomics, and mass spectrometry to bridge this knowledge gap.
Their collaborative efforts, supported by the newly established Herbert Singer Award for Collaborative Innovation, aim to uncover how metabolic remodeling reshapes the functional proteome of cancer cells and identify potential therapeutic targets. The researchers are particularly interested in understanding how metabolic alterations regulate protein function during tumor progression and metastasis.
By leveraging novel mass spectrometry-enabled chemical proteomic techniques, they can measure functional alterations across thousands of proteins simultaneously, focusing on the reactivity of chemically sensitive amino acids. This approach allows them to detect changes in protein oxidation, conformational rearrangements, and altered protein interactomes, providing a more comprehensive view of protein function than traditional protein expression studies.
The collaboration initially centered on investigating how oxidative stress influences cysteine reactivity in cancer cells. However, their recent research, now published on the bioRxiv preprint server, has revealed that these advanced chemical proteomic platforms can also reveal new insights into protein-metabolite interactions at the proteome scale.
By building a comprehensive atlas of how individual metabolites influence cysteine reactivity throughout the proteome, the researchers aim to develop a reference dataset for interpreting cysteine reactivity changes in complex biological systems, including cancer cells. This endeavor will help distinguish whether changes in cysteine reactivity are due to oxidation, metabolite binding, or other functional mechanisms.
The team has already demonstrated the impact of a protein called SLC33A1 in maintaining appropriate redox conditions within the endoplasmic reticulum (ER), a crucial metabolic hub where fats and proteins are synthesized and folded. In cancer cells with redox metabolite imbalances, boosting SLC33A1 activity could restore redox balance.
The researchers are now extending their studies to map protein-metabolite interactions and redox regulation across other organelles and whole cells, generating the first large-scale map of these functional changes. Ultimately, their goal is to identify cancer-specific signatures that reveal how metabolites alter protein function in the disease.
The researchers anticipate that detecting these unique signatures could lead to the discovery of new therapeutic targets for cancer drugs, such as Sotorasib and Adagrasib, which have already shown success in targeting KRAS_G12C mutations in non-small cell lung cancer. By understanding how metabolites regulate protein function in immune and cancer cells, this collaborative research represents a transformative approach to expanding our knowledge and developing novel strategies for cancer treatment.
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