Biology subjects

Jones, K. M.

Publications and source records attributed to Jones, K. M..

6 recordsLinked to original sources

bioRxiv2026

Aspartate aminotransferase is required for Salmonella expansion in the inflamed gut via TCA anaplerosis

Aspartate represents an important proteogenic amino acid in all living organisms. Many microorganisms can produce aspartate through various biosynthetic processes, utilizing it for energy production and as a precursor for synthesizing other biomolecules, such as amino acids and nucleotides. The enteric pathogen Salmonella Typhimurium (S. Tm) has developed mechanisms to access aspartate as a nutrient source during expansion in the inflamed gut. However, how S. Tm deals with aspartate starvation during infection remains unknown. To address this knowledge gap, we interrogated Salmonellas reliance on the bi-directional aspartate aminotransferase encoded by aspC for growth in vitro and during host colonization using murine models of Salmonella infection. AspC can interconvert aspartate and the TCA intermediate oxaloacetate and is hypothesized to support S. Tm cellular demands for aspartate during starvation or support refueling of the TCA cycle via oxaloacetate synthesis. Herein, we find that loss of aspC results in a gut-specific S. Tm colonization defect that increases with the course of infection. Importantly, aspC is dispensable for S. Tm systemic colonization in CBA/J mice. Additionally, we report that loss of aspC results in a significant growth defect during respiration of inflammation-derived electron acceptors in vitro. Interruption of oxidative TCA cycle progression via TCA enzyme deletion or supplementation with TCA intermediates (e.g., oxaloacetate) abrogates the defect observed in {Delta}aspC S. Tm in vitro. Thus, suggesting the requirement for AspC to catabolize aspartate and support the TCA cycle during respiration. Altogether, we report that AspC plays a critical role in S. Tm pathogenesis in a gut-specific manner during inflammation through supporting energy generation.

microbiology↗

bioRxiv2025

Revealing the Drivers Underlying Distinct Evolutionary Trajectories in Lung Adenocarcinoma

Elucidating the evolution of cancers allows us to understand their key events, and the order in which they occur. To chart and interpret these evolutionary trajectories, we leverage whole-genome sequencing of lung tumours, including those from the largest cohort to date of lung cancers in subjects who have never smoked. Through ordering frequent genomic alterations, we discover three distinct evolutionary paths taken by lung adenocarcinomas; two dominated by tumours from people who have never smoked (NS-LUAD), and one followed by the vast majority of those who have smoked (S-LUAD). However, one in six NS-LUAD follow the smoking-dominant trajectory. These tumours, surprisingly, have fewer somatic alterations than the other NS-LUAD, and have shorter latency. They are strongly enriched for KRAS mutations. Our results suggest that gaining KRAS mutations allows these tumours to evolve more rapidly, acquiring a set of smoking-associated key alterations, with less need for genomic instability to progress. These tumours are three times more frequent in subjects of European vs. East Asian ancestry. These findings could shape clinical management strategies for lung adenocarcinoma patients, particularly for tumours driven by smoking-like evolutionary trajectories.

cancer biology↗

bioRxiv2025

Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition

Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Re-activated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695, a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

genomics↗

bioRxiv2024

Chromosomal instability increases radiation sensitivity

Continuous chromosome missegregation over successive mitotic divisions, known as chromosomal instability (CIN), is common in cancer. Increasing CIN above a maximally tolerated threshold leads to cell death due to loss of essential chromosomes. Here, we show in two tissue contexts that otherwise isogenic cancer cells with higher levels of CIN are more sensitive to ionizing radiation, which itself induces CIN. CIN also sensitizes HPV-positive and HPV-negative head and neck cancer patient derived xenograft (PDX) tumors to radiation. Moreover, laryngeal cancers with higher CIN prior to treatment show improved response to radiation therapy. In addition, we reveal a novel mechanism of radiosensitization by docetaxel, a microtubule stabilizing drug commonly used in combination with radiation. Docetaxel causes cell death by inducing CIN due to abnormal multipolar spindles rather than causing mitotic arrest, as previously assumed. Docetaxel-induced CIN, rather than mitotic arrest, is responsible for the enhanced radiation sensitivity observed in vitro and in vivo, challenging the mechanistic dogma of the last 40 years. These results implicate CIN as a potential biomarker and inducer of radiation response, which could provide valuable cancer therapeutic opportunities. Statement of SignificanceCancer cells and laryngeal tumors with higher chromosome missegregation rates are more sensitive to radiation therapy, supporting chromosomal instability as a promising biomarker of radiation response.

cancer biology↗

bioRxiv2020

Novel epigenetic clock for fetal brain development predicts fetal epigenetic age for iPSCs and iPSC-derived neurons.

Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and iPSC-derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.

neuroscience↗

bioRxiv2020

Alterations to the cardiac metabolome induced by chronic T. cruzi infection relate to the degree of cardiac pathology

Chronic Chagasic cardiomyopathy (CCC) is a Neglected Tropical Disease caused by the parasite Trypanosoma cruzi. The pathognomonic findings in symptomatic CCC patients and animal models includes diffuse cardiac fibrosis and inflammation with persistent parasite presence in the heart. This study investigated chemical alterations in different regions of the heart in relation to cardiac pathology indicators to better understand the long-term pathogenesis of this neglected disease. We used data from echocardiography, fibrosis biomarkers, and histopathological analysis to fully evaluate cardiac pathology. Metabolites isolated from the pericardial and endocardial sides of the right ventricular myocardium were analyzed by liquid chromatography tandem mass spectrometry. The endocardial sections contained significantly less cardiac inflammation and fibrosis than the pericardial sections. Cardiac levels of acylcarnitines, phosphocholines, and other metabolites were significantly disrupted in accordance with cardiac fibrosis, inflammation, and serum fibrosis biomarker levels. These findings have potential implications in treatment and monitoring for CCC patients.

microbiology↗