Biology subjects

Yu, E. A.

Publications and source records attributed to Yu, E. A..

3 recordsLinked to original sources

bioRxiv2025

Early-life nutrition supplementation and epigenetic age in middle-adulthood among Guatemalan adults

ObjectivesEpigenetic clocks are biomarkers of aging. Epigenetic clocks are associated with early-life famine exposure. We investigated the impact of a cluster-randomized early-life nutrition intervention on epigenetic age. MethodsWe analyzed follow-up data from participants in the INCAP Nutrition Supplementation Trial, conducted in 4 villages in eastern Guatemala. DNA methylation was measured in buffy coat samples using the Illumina InfiniumTM MethylationEPICv2.0 array and standard quality control procedures. Epigenetic age was quantified using DunedinPACE, PhenoAge, and GrimAge. PhenoAge and GrimAge acceleration were calculated as residuals by regressing epigenetic age on chronological age. We used intent-to-treat difference-in-difference modeling to assess the impact of a protein-energy supplement provided during the first 1,000 days of life (conception to age 2y) on epigenetic age in middle adulthood. Covariates included sex, birth year, the trial supplement type (atole [intervention] vs. fresco [control]), exposure period of supplement (any of the first 1,000 days, other), and a random effect to account for sibships. The primary coefficient of interest was represented by the interaction between supplement type and exposure period. ResultsThe analysis included 1095 participants (mean age 45.0 y (SD 4.3); 60.3 % female, 40.3 % exposed to any atole during the first 1,000 days, mean DunedinPACE 1.2 (SD 0.1), Phenoage 46.7 y (SD 6.7), and GrimAge 56.3 y (SD 4.1). In difference-in-difference analyses, exposure to atole during any of the first 1,000-day period was associated with lower DunedinPACE (- 0.03, 95% CI -0.06, -0.004), PhenoAge acceleration (- 1.91 y, 95% CI -3.43, -0.39), and GrimAge acceleration (-0.85 y, 95% CI -1.53, -0.11) compared to other exposures. Following additional adjustment for cell type proportions, the direction of the coefficients remained the same but were no longer statistically significant. ConclusionsExposure to atole during the first 1,000 days was associated with modest reductions in epigenetic age as measured by DunedinPACE, PhenoAge, and GrimAge. These findings complement prior evidence of epigenetic age acceleration among individuals with early-life famine exposure.

genomics↗

bioRxiv2020

Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

Introductory paragraphThe clinical success of targeted cancer therapy is limited by drug resistance that renders cancers lethal in patients1-4. Human tumours can evolve therapy resistance by acquiring de novo genetic alterations and increased heterogeneity via mechanisms that remain incompletely understood1. Here, through parallel analysis of human clinical samples, tumour xenograft and cell line models and murine model systems, we uncover an unanticipated mechanism of therapy-induced adaptation that fuels the evolution of drug resistance. Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenic EGFR-driven and ALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity of APOBEC3B via therapy-mediated activation of NF-{kappa}B signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutant EGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy.

cancer biology↗

bioRxiv2019

Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing

Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNAseq) of metastatic lung cancer was performed using 44 tumor biopsies obtained longitudinally from 27 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNAseq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNAseq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.

cancer biology↗