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62 Publications visible to you, out of a total of 62
DNA adduct and mutational profiles reveal a threshold of cellular defenses against N-nitrosodimethylamine administered to mice in drinking water.

Abstract (Expand)

N-Nitrosodimethylamine (NDMA) is classified as an animal and probable human carcinogen. Murine liver DNA adducts, mutations, O (6)-methylguanine DNA methyltransferase (MGMT), and CYP2E1 were evaluated … following chronic administration of NDMA in drinking water. In a dose-escalation study, 7-methylguanine (m7G) increased linearly with NDMA dose. O (6)-Methylguanine (m6G) remained near background for NDMA doses up to approximately 1 ppm, beyond which its level, and corresponding mutations, rose steeply. An extended study was done with 5 ppm NDMA, in which adducts were measured at 3 and 10 weeks and mutations at 10 weeks. We found that both sexes experienced elevated levels of point mutations closely tracking with the levels of m6G, which emerged as the dominant mutagenic adduct under chronic dosing with NDMA. Homologous recombination-mediated chromosomal rearrangements, however, did not increase over background. Mutational analysis over 96 trinucleotide contexts revealed predominantly GC-->AT mutations in 5'-purine-G-3' contexts in a pattern matching human COSMIC cancer mutational signature SBS11, with secondary features resembling SBS119 (AT-->GC). Moreover, we identified the m6G level ( approximately 2000 adducts/diploid genome) above which its dedicated repair protein, MGMT, became saturated. The coordinated application of DNA adduct, mutational, and biochemical analyses provides a new approach for studying mechanisms of carcinogenesis, with relevance to early cancer detection and cancer management.

Authors: N. E. Gubina, L. B. Volk, A. F. Dormitzer, E. M. Michelsen, L. J. Pribyl, J. J. Corrigan, E. D. Dalvie, A. L. Armijo, M. Norales, N. A. Bugher, K. M. Schonvisky, D. L. Plata, B. P. Engelward, R. G. Croy, J. M. Essigmann, B. I. Fedeles

Date Published: 15th Jul 2026

Publication Type: Journal

Tyrosine phosphoproteome profiling identifies cell-intrinsic signals limiting the efficacy of tyrosine kinase inhibitor therapies.

Abstract (Expand)

Tyrosine kinases (TKs) are frequently mutated or overexpressed in cancer, and TK inhibitors (TKIs) are an important therapeutic modality against TK-driven cancers, but many patients show an underwhelming … response to TKIs prescribed on the basis of tumor genotype. To find cell-intrinsic TK signaling patterns which might be predictive of poor response to TKI therapies, we used high-sensitivity multiplexed mass spectrometry to quantify endogenous levels of 1,222 phosphotyrosine (pY) sites across the proteomes of TK-driven human cancer cell lines with variable response to genotype-matched TKIs. In direct comparisons between TKI-tolerant and TKI-sensitive lines with a common driver TK, we found that TKI treatment was equally effective at blocking driver TK signaling, and higher basal activity of the driver TK did not always predict higher sensitivity to TKI. All tolerant lines showed a dampened proteome-wide pY response to TKI exposure compared to sensitive lines, suggesting that tumor cells with more robust TK signaling are less vulnerable to driver TK blockade. We found that each tolerant line depends on a unique set of compensatory TKs and signaling axes but are unified by hyperactivity of at least one of the SRC family kinases (SFKs) or the related ABL1/2 kinases, both at rest and under TKI treatment, despite the absence of SFK or ABL genetic mutations. In time- and dose-resolved drug combination experiments, SFK/ABL inhibitors were potently synergistic with all TKIs tested, demonstrating that elevated SFK/ABL signaling is a conserved bottleneck for maximal TKI efficacy which could be exploited therapeutically.

Authors: C. T. Flower, F. M. White

Date Published: 31st Mar 2026

Publication Type: Journal

Quantitative Cell Type-Specific Immunopeptidome Analysis of Macrophage and Tumor Coevolution Reveals Therapeutic MHC-I Peptides in Glioblastoma.

Abstract (Expand)

Immune checkpoint inhibitors have shown impressive performance in treating several types of solid tumors. However, they have been ineffective in glioblastoma (GBM), in part due to the immunosuppressive … tumor microenvironment created by GBM-associated macrophages (GAM). To uncover MHC-I peptide antigens for targeted immunotherapy, we performed cell type-specific immunopeptidome analysis on primary macrophages and GBM tumor cells in a coculture system to profile MHC-I-associated antigen presentation at the tumor-macrophage interface. Coculturing tumor cells and macrophages induced increased presentation of peptides derived from proteins associated with cytokine signaling pathways on macrophages and from proteins associated with the Rho GTPase pathway on GBM tumor cells. In vivo expression was validated for a cohort of coculture-induced GAMs or GBM-associated peptides selected as potential immunotherapy targets, and an mRNA vaccine was developed encoding six peptides from GAMs and GBM tumor cells. Two doses of vaccination generated an antigen-specific immune response, significantly delayed GBM tumor growth, and in some cases eradicated tumors. These results demonstrate the translational potential of coculture-induced MHC peptide antigens as therapeutic targets for GBM/GAM-targeting vaccines. SIGNIFICANCE: Immunopeptidomic analysis identified altered expression of antigens during macrophage-tumor coevolution that could be targeted with an mRNA vaccine to significantly inhibit glioblastoma growth, revealing potential immunotherapeutic strategies for treating tumors.

Authors: Y. Cui, K. Phuong, N. S. Abdelfattah, H. M. Temple, L. Maiorino, B. J. Kim, J. Dye, K. K. H. Yu, S. Spranger, D. J. Irvine, F. M. White

Date Published: 15th Dec 2025

Publication Type: Journal

Immunopeptidomics can inform the design of mRNA vaccines for the delivery of Mycobacterium tuberculosis MHC class II antigens.

Abstract (Expand)

No currently licensed vaccine reliably prevents pulmonary tuberculosis (TB), a leading cause of infectious disease mortality. Developing effective new vaccines requires identifying which Mycobacterium … tuberculosis (Mtb) proteins are presented on major histocompatibility complex class II (MHC-II) by infected human phagocytes (target cells) and defining their capacity for recognition by CD4(+) T cells. Vaccine designs must elicit T cell responses recognizing the same peptide-MHC complexes presented by infected cells. Although many human CD4(+) T cell Mtb epitopes have been described, presentation on MHC-II by infected cells in most cases has not been directly evaluated. Using mass spectrometry (MS), we demonstrated that Mtb type VII secretion system (T7SS) substrates are enriched in the MHC-II repertoire of Mtb-infected human monocyte-derived phagocytes and that many of these antigens are immunogenic in people with prior evidence of Mtb infection. We next used MS to guide TB messenger RNA (mRNA) vaccine design, increasing the presentation of target MHC-II epitopes by orders of magnitude by incorporating design features that mirror aspects of antigen presentation dynamics in infected phagocytes. Our results provide a strategy for TB vaccine design that is guided by bottom-up unbiased discovery. Our approach combines targeted evaluation of antigen presentation in human cells paired with rapid iterative testing of mRNA vaccine designs to optimize antigen presentation before animal studies or human clinical trials.

Authors: O. Leddy, P. Ogongo, J. Huffaker, M. Gan, R. Milligan, S. Mahmud, H. M. Ni, Y. Yuki, K. Bobosha, L. Wassie, M. Carrington, Q. Liu, J. D. Ernst, F. M. White, B. D. Bryson

Date Published: 5th Nov 2025

Publication Type: Journal

IFN-γ- GranzymeB + Natural killer cells are induced by IV BCG vaccination and associated with protection against tuberculosis in rhesus macaques.

Abstract

Not specified

Authors: Mohau S. Makatsa, Emma Bishop, Allison N. Bucsan, Matthew S. Sutton, Chelsea C. Lehman, Molly Robertson, Krystle K.Q. Yu, Joshua M. Peters, Bryan D. Bryson, Mario Roederer, Robert A. Seder, Patricia A. Darrah, Chetan Seshadri

Date Published: 1st Nov 2025

Publication Type: Journal

BCG vaccination elicits protection against Mtb infection mediated by two phases of T cell immunity

Abstract

Not specified

Authors: Abiola F. Ogunsola, Rocky Lai, Kelly Cavallo, Gillian L. Beamer, Samuel M. Behar

Date Published: 30th Oct 2025

Publication Type: Journal

Rewiring of cortical glucose metabolism fuels human brain cancer growth.

Abstract (Expand)

The brain avidly consumes glucose to fuel neurophysiology(1). Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy … tissue(2). How brain cancers rewire glucose use to drive aggressive growth remains unclear. Here we infused (13)C-labelled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumour versus cortex. Through direct and comprehensive measurements of carbon and nitrogen labelling in both cortex and glioma tissues, we identify profound metabolic transformations. In the human cortex, glucose carbons fuel essential physiological processes, including tricarboxylic acid cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters glioblastoma metabolism, slows tumour growth and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumours exploit glucose to suppress normal physiological activity in favour of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.

Authors: A. J. Scott, A. Mittal, B. Meghdadi, A. O'Brien, J. Bailleul, P. Sravya, A. Achreja, W. Zhou, J. Xu, A. Lin, K. Wilder-Romans, N. Liang, A. U. Kothari, N. Korimerla, D. M. Edwards, Z. Wu, J. Feng, S. Su, L. Zhang, P. Sajjakulnukit, A. C. Andren, J. O. Park, J. Ten Hoeve, V. Tarnal, K. A. Redic, N. R. Qi, J. L. Fischer, E. Yang, M. S. Regan, S. A. Stopka, G. Baquer, K. Suresh, J. N. Sarkaria, T. S. Lawrence, S. Venneti, N. Y. R. Agar, E. Vlashi, C. A. Lyssiotis, W. N. Al-Holou, D. Nagrath, D. R. Wahl

Date Published: 9th Oct 2025

Publication Type: Journal

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