- by Lin, X., Liu, X., Nicolazzi, G., Zick, Y., Brown, J. W.ABSTACTGalectin-8 is a lectin that binds N-acetyllactosamine moieties with preference towards those with acidic, terminal modifications (-O-sialyated, 3-O-sulfated). As CD44-variants (CD44v) are biomarkers of metaplasia and cancer, a hyaluronic acid receptor that modulates STAT3 signaling, and specifically expresses 3-Sialyl-LeA/X glycotopes, we asked whether galectin-8 might play a role in gastric metaplasia. Using a synchronous, chemically induced murine model that produces gastric spasmolytic polypeptide expressing metaplasia (SPEM), we compared Lgals8-/- mice to congenic wild-type C57BL/6J mice. We found that galectin-8 was […]
- by Macias Palacio, S., Rummel, N., Campbell, J., Butterfield, D. A., Bondada, S., Wang, C., Faisal, A. S. M., Villano, J., Bauer, B., St Clair, D., Chaiswing, L.Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Cognitive impairment is a common sequela in glioblastoma survivors, yet the underlying mechanisms remain poorly understood. Extracellular vesicles (EVs) derived from glioblastoma are established mediators of intercellular signaling within the tumor microenvironment. Here, we investigated whether GBM-derived EVs released after radiation treatment (RT-EVs) regulate cognitive function. Treatment with RT-EVs was associated with cognitive deficits and neuroinflammatory responses in vivo. In vitro, RT-EVs activated the NF{kappa}B pathway and induced the […]
- by Lin, X., Liu, X., Nicolazzi, G., Pan, A., Hua, M., Brown, J. W.The expression and secretion of sulfated colonic-type mucins is a feature of high-risk metaplasias of the gastrointestinal foregut (Barretts esophagus, type III intestinal metaplasia of the stomach, and pancreatic intraepithelial neoplasia). Galectin-3 is a lectin that preferentially associates with galactose modified by a 3-O-sulfate relative to its unmodified counterparts and is upregulated as the tissue transitions to high-risk metaplasia, dysplasia, and cancer. Since both galectin-3 and sulfated glycotopes are aberrantly and concurrently overexpressed in high-risk premalignant and malignant tissue transformations, […]
- by Eder, I., Baghaei, M., Maurya, S., Yu, V., Wilson, E., Kashkoush, A., Liu, J.-J., Liu, S., Luo, J., Storkus, W., Roy, P.Dysregulation of actin-binding protein Profilin1 (Pfn1) in tumor cells has prominent impacts on the tumor-intrinsic aspects of tumor progression. However, whether and how modulation of Pfn1 expression in tumor cells influences immune surveillance in cancer is not known. We utilized an inducible CRISPR/Cas9 knockout (KO) model to first demonstrate that triggering Pfn1 depletion in breast cancer cells leads to features of genomic instability (polyploidy, micronuclei, and DNA damage) and intrinsic defects in both homologous-recombination- and non-homologous end-joining-mediated double-stranded DNA repair. […]
- by Sato, H., Sato, T., Sasagawa, Y., Seki, R., Zhang, S., Haeno, H., Hishikawa, D., Sakai, M., Hata, K., Nikaido, I., Mori, Y., Noguchi, T., Ohteki, T.While a subpopulation termed cycling persisters (CPs) that is characterized by sustained proliferation, even under chemotherapy drug exposure, contributes more directly to tumor relapse, the molecular basis for the emergence of CPs has been unclear. Here, we used the human tongue cancer organoid (TCO) library to continuously track the in vitro fate of individual cancer cell clones during and after chemotherapy exposure using time-lapse imaging. Among the heterogeneous clones, we identified CPs that formed larger clusters than the others, which […]
- by Shi, H., Yin, W., Zhang, H., Jiang, X., He, J., Zhu, G., Overstreet, M. G., Cobbold, M., Shen, L.Chimeric antigen receptor (CAR)-T cell therapy has improved outcomes for patients with multiple myeloma (MM), but its broader use is restricted by manufacturing complexities and treatment-related toxicities. AZD0120 is a dual-targeting B-cell maturation antigen (BCMA)/CD19 CAR-T cell therapy manufactured via the rapid FasTCAR process. We developed a dual-targeting "loop" CAR that incorporates a novel humanized anti-BCMA single-chain variable fragment (scFv), clone SG, and an FMC63-derived anti-CD19 scFv. This AZD0120 CAR preserved functional binding to both antigens and conferred robust in […]
- by Kitanovski, S., Srinivas, N., Schrama, D., Hoffmann, D., Becker, J.Primary tumors and their sentinel lymph nodes are functionally linked sites of anti-tumor immunity, yet how T cell receptor (TCR) repertoires are organized across these compartments remains incompletely understood. We thus performed TCR{beta} sequencing on paired primary melanoma tumors and sentinel lymph nodes from 24 treatment-naive patients to quantify TCR repertoire diversity and clonal architecture as markers of antigen-driven selection. Primary tumors exhibited markedly reduced TCR diversity and pronounced clonal dominance compared with matched lymph nodes, consistent with selective expansion […]
- by Olmedo-Pelayo, J., Lobo-Selma, L., Delgado-Bellido, D., Jordan-Perez, C., Gilabert-Prieto, P., Perez, M., Geyer, F. H., Carreno-Gonzalez, M. J., Alonso, J., Zheng, L., Shen, B., Grunewald, T. G. P., Gomez Herreros, F., de Alava, E.Ewing sarcoma (EwS) is an aggressive malignancy driven by EWSR1::ETS fusions, predominantly EWSR1::FLI1. Previous efforts using both direct and indirect approaches to target these chimeric oncoproteins have yielded limited clinical benefit. Although EWSR1::FLI1 is a well-known source of replication stress and genome instability, targeting DNA damage response (DDR) factors that mitigate these effects remain poorly understood. Here, we identified a marked dependency of EwS cells on exonuclease 1 (EXO1). We demonstrate that EXO1 is essential for EwS cell survival and […]
- by Varona Baranda, M., Liesenfelder, S., Kraft, F., Kuo, C.-C., Perez-Correa, J.-F., Jost, E., Stiehl, T., Wagner, W.Epigenetic dysregulation is a defining feature of cancer, but it remains poorly understood how this is coordinated across the genome. In this study we focusd on DNA methylation (DNAm) in acute myeloid leukemia (AML). Despite highly heterogeneous and largely patient-specific patterns, we identified co-regulated clusters of CpGs that could be assembled into reproducible epigenetic networks. Multilinear regression models accurately predicted the patient-specific DNAm deviations, even for CpGs located on different chromosomes. The alterations were mirrored on homologous chromosomes and there […]
- by Khazan, N., Snyder, C. W., Dawney, N., Lamere, E., Ekambaram, S., Singh, N. A., Ravi, C., Snape, R., Aichelman, H., Pritchette, E., Ashton, J. M., Kay, T., Strawderman, M., Yano, N., Bergstralh, D. T., Eichfeld, G. C., Hansen, J. N., Ewers, H., Kim, K. K., Rowswell-Turner, R. B., Gerber, S. A., Tabdanov, E., Bertin, A., Dokholyan, N., Moore, R. G., Singh, R.In cancer cells, septins assemble into enigmatic higher-order structures of 300-700 nanometers, including long needle-like filaments, thick perinuclear rings, and cytoplasmic bundles or aggregates. The absence of genetic or pharmacological tools to recapitulate these architectures in-vitro has impeded mechanistic studies of their formation, function, and therapeutic targeting. Here, first, determining the overexpression of septin-2 in epithelial ovarian cancer (EOC) and its association with increased mortalities and dependencies, we select SKOV-3 ovarian cancer cells as a tractable model in which septin […]
- by Johri, S., Pimenta, E. M., Yates, J., Fu, J., Bao, E. L., Jun, H., Reardon, B., Bacot, S., Shady, M., Fu, D., Mei, W., Camp, S. Y., Park, J., Van Allen, E.Advances in large language models (LLMs)-based artificial intelligence (AI) agents have improved their ability to execute structured analytical workflows, including standard bioinformatic pipelines for biological discovery. However, computational biology rarely consists of deterministic pipeline execution alone. Biological datasets are heterogeneous and noisy, and meaningful discovery often requires open-ended hypothesis generation and iterative reasoning over multimodal evidence. These challenges are particularly evident in multi-omic studies, where paired molecular modalities and heterogeneous clinical contexts create both opportunities and obstacles for discovery. The […]
- by Solimo, A. M., Sciacca, M., Cascardo, F., Finkielsztein, L., Eijan, A. M., Lodillinsky, C., Callero, M. A.T2, an N4-aryl-substituted thiosemicarbazone, has previously been shown to exert cytotoxic and anti-invasive effects in triple-negative breast cancer (TNBC) and to increase expression of the metastasis suppressor N-myc downstream-regulated gene 1 (NDRG1). Given the role of NDRG1 in regulating epithelial-mesenchymal transition (EMT) and WNT/{beta}-catenin signaling, we investigated the contribution of this pathway to the anti-invasive activity of T2. The effects of T2 on WNT/{beta}-catenin signaling and associated microRNAs (miR-182-5p and miR-200c) were evaluated in 4T1 cells. In vivo activity was […]
- by Azzi, A., El Sayed, A. R.Fluoropyrimidine-based chemotherapies, including 5-fluorouracil (5-FU) and floxuridine (FuDR), are widely used in cancer treatment, but their efficacy is limited by adaptive resistance driven by TYMS upregulation. The upstream mechanisms controlling TYMS expression remain poorly defined. Here, we identify INPPL1 (SHIP2) as a critical regulator of TYMS expression and fluoropyrimidine response in breast cancer cells. We show that SHIP2 enhances basal and drug-induced TYMS expression at the transcriptional level independently of its phosphatase activity. Mechanistically, SHIP2 increases SRC levels and nuclear […]
- by Fashemi, B. E., Ota, Y., Gupta, V., Elizagaray, M. L., Pique-Regi, R., Gomez-Lopez, N., Mullen, M., Khabele, D.High-grade serous ovarian carcinoma (HGSOC) is characterized by widespread peritoneal dissemination and poor long-term survival, largely driven by metastatic relapse following initial response to chemotherapy. Defining the molecular programs that enable tumor progression from the primary ovarian site to metastatic niches remains a key challenge. Here, we leverage patient-derived organoids (PDOs) coupled with single-cell RNA sequencing (scRNA-seq) to interrogate tumor evolution and identify regulators of metastatic competence in HGSOC. We profiled PDOs and matched formalin-fixed paraffin-embedded (FFPE) tumor samples from […]
- by Herrgott, G., Garofano, L., Silva Morosini, N., Done, B., Powell, C. L., deCarvalho, A., Hasselbach, L., Transou, A., Lee, I., Walbert, T., Snyder, J., Lasorella, A., Castro, A. V., Iavarone, A., Noushmehr, H.IDH-mutant gliomas stratified by glioma CpG island methylator phenotype (G-CIMP) into High (GCH) and Low (GCL) exhibit markedly divergent clinical outcomes, yet cellular and regulatory determinants of this distinction remain incompletely defined. Integrating single-nucleus RNA-and ATAC-sequencing across 18 tumor specimens from 10 patients, we resolved six malignant cellular states whose differential enrichment across G-CIMP strata delineates the GCL epigenomic transition. GCL tumors were enriched for independently prognostic Mesenchymal and Mitotic Proliferative states, driven by convergent E2F, MYC, MEF2, and NFI-family […]
- by Monnone, A., Nicknish, M., Montezco, J. J., Sanganoo, C., Aggarwal, N., Luong, A., Schaus, S., Grinstaff, M.Reactive oxygen species (ROS) are key mediators of disease, yet accurate characterization in living systems remains challenging because current probes lack oxidation specificity and produce nonlinear, pH-dependent signals. Here we introduce Rosindol, a novel thioacetal-based fluorogenic probe that overcomes these limitations. Rosindol undergoes an umpolung oxidation in the presence of ROS to generate fluorescence, displaying dose-linear responses to H2O2, O2*-, OH*, and HOCl with minimal background signal. Unlike conventional probes, Rosindol is pH-independent, photostable, water soluble, and agnostic to glucose […]
- by MAMANN, A., Das, J., Benkirane, H., Bugiotti, F., Bernard, E., Besse, B., Michiels, S., Cournede, P.-H.Longitudinal circulating tumor DNA (ctDNA) measurements offer a noninvasive means to monitor treatment response, but clinical trial data present substantial methodological challenges due to high-dimensional short longitudinal ctDNA sequences and limited sample sizes. We introduce SHERLOC, a deep learning framework specifically designed for survival analysis using longitudinal on-treatment ctDNA data, which integrates shared temporal representations of gene-level variant allele frequencies, feature-specific temporal trajectories of panel-level ctDNA biomarkers, and survival-aware genomic representations pre-trained on a large pan-cancer tissue-biopsy dataset (MSK-CHORD), within […]
- by Schwager, A., Grishina, Y., Tsimailo, I., Rashidova, G., Tiukacheva, E., Pestriakov, M., Lagorgette, L., Bogdanova, D., Garaev, A., Michot, J.-M., Ribrag, V., Demidov, O., Andrieu, G., Ulianov, S., Razin, S., Germini, D., Vassetzky, Y.Mantle cell lymphoma (MCL) is defined by the t(11;14)(q13;q32) translocation, which drives constitutive CCND1 expression, yet the broader regulatory consequences of this rearrangement remain incompletely understood. Here, we combined transcriptomic, epigenomic, Hi-C, and 3D-FISH analyses in primary MCL samples and cell lines to investigate the genome-wide impact of t(11;14) on chromatin organization and gene regulation beyond the rearranged chromosomes. We show that MCL cells exhibit widespread enhancer activation, accompanied by expansion of super-enhancer regions. The translocated CCND1 locus repositions toward […]
- by Manojlovic, V., Gabbutt, C., Shibata, D., Noble, R. J.Determining the nature of human tumour growth is challenging given the impracticality of obtaining detailed data across time. A promising solution is to examine DNA regions whose methylation states fluctuate on clinically relevant timescales, permitting their use as high-resolution lineage tracers. However, existing methods developed for analysing the fluctuating methylation loci of normal tissue and lymphoid cancers are inapplicable to large solid tumours. Here we introduce a mechanistic computational model that tracks the evolution of heritable methylation marks as a […]
- by Tavakoli Shirazi, P., Straube, J., Ling, V., Andersen, S., Cooper, E., Chan, S. H. N., Haldar, R., Janardhanan, Y., Cooper, L., Bruedigam, C., Grove, C., Bywater, M., Lane, S.Concurrent mutations in DNMT3A, NPM1, and FLT3 define a high-risk subtype of acute myeloid leukemia (AML) associated with increased relapse risk and inferior survival following standard chemotherapy. However, the mechanisms by which DNMT3A mutations promote treatment resistance in NPM1c-FLT3ITD AML remain unclear. Using genetically engineered murine models of Npm1c-Flt3ITD AML with or without Dnmt3aR878H (homologous to human DNMT3AR882H), we demonstrate that Dnmt3aR878H promotes chemotherapy resistance through epigenetic regulation of leukemia stem cell (LSC) quiescence. Integrated transcriptomic and epigenetic profiling revealed […]
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