Biology subjects

Ryseck, R.-P.

Publications and source records attributed to Ryseck, R.-P..

4 recordsLinked to original sources

bioRxiv2025

Many circulating indole and phenol metabolites are host derived

Indole and phenol metabolites are typically thought to be products of bacterial digestion of tryptophan (indoles) and phenylalanine or tyrosine (phenols). Interest in controlling gut microbial production of these metabolites has continually grown as they have important physiological impacts, with indoles agonizing AhR signaling, and phenols being associated with healthy body weight. While there is a growing wealth of research into which bacteria produce these metabolites, host contribution to their circulating pools has not been adequately characterized. Here, through stable isotope tracing in cell culture and mice, we show that mammalian cells can make aryl-pyruvates, -lactates, -acetates, and -carboxylic acids. Levels of these metabolites in mice and human patients are insensitive to perturbations of the microbiome. In contrast, bacterial metabolism is required to synthesize aryl-propionates and free indole, phenol, and cresol. Overall, we show that host metabolism is a primary contributor to circulating indole and phenol metabolite pools.

molecular biology↗

bioRxiv2025

High-fat circulating nutrients promote growth and invasion in a 3D microfluidic tumor model of triple-negative breast cancer

Diet influences the levels of small molecules that circulate in plasma and interstitial fluid, altering the biochemical composition of the tumor microenvironment (TME). These circulating nutrients have been associated with how tumors grow and respond to treatment, but it remains difficult to parse their direct effects on cancer cells. Here, we combine a three-dimensional (3D) microfluidic tumor model with physiologically relevant culture media to investigate how concentrations of circulating nutrients influence tumor growth, cancer cell invasion, and overall tumor metabolism. Human triple-negative breast cancer cells cultured in 2D under media conditions mimicking five different dietary states show no observable differences in proliferation or morphology. Nonetheless, those exposed to high-fat conditions exhibit increased metabolic activity and upregulate genes associated with motility and extracellular matrix remodeling. In the 3D microfluidic model, high-fat conditions accelerate tumor growth and invasion and induce the formation of hollow cavities. Surprisingly, the presence of these cavities does not correlate with an increase in apoptosis or ferroptosis. Instead, RNA-sequencing analysis revealed that high-fat conditions induce the expression of MMP1, consistent with cavitation via cell invasion. Mimicking the flow of circulating nutrients within the TME can thus be used to identify novel connections between metabolic states and tumor phenotype.

bioengineering↗

bioRxiv2024

Integrative Computational Framework, Dyscovr, Links Mutated Driver Genes to Expression Dysregulation Across 19 Cancer Types

Mutations within cancer driver genes induce widespread transcriptional changes that reflect altered cellular states and can reveal associated genetic vulnerabilities. However, it remains challenging to determine which genes are dysregulated as a consequence of cancer alterations, and of these, which represent therapeutic opportunities. Here, we present Dyscovr, an integrative computational framework that leverages somatic mutation, gene expression, copy number alteration, methylation, and clinical data from primary tumors to identify driver-associated transcriptional changes. Dyscovr then uses these transcriptional changes as a biologically grounded starting point, integrating them with cancer cell line data to prioritize genes whose inhibition is predicted to reduce viability either specifically in driver-mutant contexts or in combination with driver inhibition. Applied both pan-cancer and across 19 tumor types, Dyscovr uncovers hundreds of such conditional vulnerabilities. As a case study, we newly implicate--and experimentally validate--KBTBD2 as a gene whose inhibition enhances the efficacy of PI3K inhibitors in PIK3CA-mutant breast cancer cell lines. The Dyscovr software (github.com/Singh-Lab/Dyscovr) and predictions (dyscovr.princeton.edu) provide a platform and resource for linking mutated driver genes to conditional genetic vulnerabilities and for prioritizing these relationships for experimental and therapeutic investigation.

systems biology↗

bioRxiv2022

Proteome capacity constraints favor respiratory ATP generation

Cells face competing metabolic demands. These include efficient use of both limited substrates and limited proteome capacity, as well as flexibility to deal with different environments. Flexibility requires spare enzyme capacity, which is proteome inefficient. ATP generation can occur via fermentation or respiration. Fermentation is much less substrate-efficient, but often assumed to be more proteome efficient 1-3, thereby favoring fast-growing cells engaging in aerobic glycolysis 4-8. Here, however, we show that mitochondrial respiration is actually more proteome-efficient than aerobic glycolysis. Instead, aerobic glycolysis arises from cells maintaining the flexibility to grow also anaerobically. These conclusions emerged from an unbiased assessment of metabolic regulatory mechanisms, integrating quantitative metabolomics, proteomics, and fluxomics, of two budding yeasts, Saccharomyces cerevisiae and Issatchenkia orientalis, the former more fermentative and the latter respiratory. Their energy pathway usage is largely explained by differences in proteome allocation. Each organisms proteome allocation is remarkably stable across environmental conditions, with metabolic fluxes predominantly regulated at the level of metabolite concentrations. This leaves extensive spare biosynthetic capacity during slow growth and spare capacity of their preferred bioenergetic machinery when it is not essential. The greater proteome-efficiency of respiration is also observed in mammals, with aerobic glycolysis occurring in yeast or mammalian cells that maintain a fermentation-capable proteome conducive to both aerobic and anaerobic growth.

systems biology↗