- by Browne, M. R., Silver, A. V., Banerjee, R., Oristian, K. M., Himes, J. E., Hendrickson, P. G., Kirsch, D. G.CIC::DUX4 sarcoma (CDS) is a lethal cancer driven by a fusion between tumor suppressor Capicua (CIC) and pioneer transcription factor double homeobox 4 (DUX4). To develop an immunocompetent pre-clinical model of CDS, we previously generated three genetically engineered mouse models (GEMMs) of CDS with CIC::DUX4 regulated by loxP-STOP-loxP cassettes. However, all three models developed spontaneous tumors without Cre recombinase. Here, we established an innovative GEMM of CDS (dFLEx CDS) that employs a dual recombinase (Cre + FLPE) FLEx-switch design to […]
- by Liu, M., Lu, L., Zhu, L., Zhang, X., Liu, Y., Ren, X., Liu, S., Cheng, S., Xu, M., lu, C., Peng, Y., Su, W., Guo, Y., Chen, S.Backgrounds: Next-generation sequencing (NGS) and droplet digital PCR (ddPCR) are both established methods for detecting EGFR mutations in non-small cell lung cancer (NSCLC). However, comprehensive validation of their concordance in mutation detection and variant allele frequency (VAF) quantification across heterogeneous sample types remains limited. Inconsistent results from different sample types (e.g., cfDNA, FFPE) pose a significant challenge to clinical decisions. This is particularly critical for advanced NSCLC patients, who often rely on liquid biopsy, yet the concordance between liquid and […]
- by Moreno, S. V., Khatun, M., Pasanen, A., Butzow, R., Salumets, A., Loukovaara, M., Modhukur, V.Relapse risk in endometrial carcinoma (EC) is strongly influenced by molecular subtype, yet current WHO/ESGO classifications rely on postoperative data, limiting their utility for preoperative decision-making. We developed and compared interpretable machine learning (ML) models to predict relapse timing (none, [≤]6 months, >6 months) using exclusively preoperative multimodal data. In a retrospective cohort of 784 EC patients, we integrated clinicopathological, molecular, immunohistochemical, and systemic biomarkers and constructed four feature strategies: (1) Traditional (clinicopathology), (2) ESGO (guideline risk groups), (3) TP53 […]
- by Tschaharganeh, D. F., Seretny, A.Objective: Primary liver cancer is a leading cause of cancer-related mortality and harbors recurrent mutations in chromatin regulators such as BRCA1-associated protein 1 (BAP1), yet their functional impact remains unclear. We investigated how BAP1 deficiency affects liver homeostasis and tumorigenesis to clarify its functional role. Design: We employed inducible, liver-specific BAP1 knockdown in mice subjected to diet-induced metabolic stress (including rescue experiments), alongside autochthonous hydrodynamic CRISPR models, and profiled livers by RNA-seq, immunohistochemistry, and mass spectrometry-based lipidomics. Complementary mechanistic assays […]
- by Lucas, A., Reale, M., Wolf, Y. I., Duong, B., Zhang, Y., Wickramasinghe, J., Behlman, L., Jones, S. M., Higgins, S., Moustafa, A. M., Elbasir, A., Amaravadi, R., Mitchell, T., Huang, A., Auslander, N.The gut microbiome has been causally linked to the efficacy of immune-checkpoint inhibitor therapy (ICI), prompting numerous clinical trials of microbiome-targeting strategies. Yet, mechanisms by which gut microbiota shape immune responses remain elusive as taxonomic biomarkers have failed to generalize across multiple cohorts. In this study, we develop a taxonomy-agnostic framework to identify microbial biomarkers of ICI response and immune-related adverse event (irAE) occurrence from metagenomic sequencing. Applying this approach to four independent melanoma cohorts from clinical centers across the […]
- by Girnius, N., Vallius, T., Chen, W., Launonen, I.-M., Palomino-Echeverria, S., Lin, J.-R., Mills, C. E., Kauppila, S., Kronqvist, P., Ellonen, A., Perala, M., Withnell, E., Chen, Y.-A., Secrier, M., Santagata, S., Sorger, P. K., Farkkila, A.Inhibiting oxidative stress response (OSR) proteins has been suggested as a therapeutic strategy in triple negative breast cancer (TNBC). However, the cell type specificity and spatial distribution of OSR genes and proteins, such as GCLC and NQO1, is unknown. Using single cell and spatial transcriptomics datasets we found that OSR genes were highly expressed in TNBC tumor cells, which localized in spatial clusters. Multiplex immunofluorescence imaging of 345 TNBC samples from 186 patients demonstrated that OSR proteins GCLC and NQO1 […]
- by Kim, S.-H.Pediatric cancers evolve under developmental constraints that limit mutational diversity yet preserve adaptive potential. A computational extension of the Hybrid Ornstein-Uhlenbeck (OU)-Branching framework was developed to model clonal diversification and phenotypic stabilization in pediatric leukemia. The OU component captures mean-reverting dynamics representing developmental homeostasis, while the branching component introduces stochastic lineage bifurcation and extinction. Using de-identified clinical metadata from Ahlgren et al. (Nature Communications, 2025; 16:8964), the model simulates patient-specific evolutionary trajectories across relapse categories and disease subtypes (B-ALL, T-ALL, […]
- by Vinothkumar, P., Lin, P.-Y., Cheng, L.-T., Yu, C.-H., Hsu, P.-H., Chou, Y.-C., Hwang-Verslues, W. W.Ovarian cancer (OC) is highly metastatic and chemoresistant. Due to heterogeneity among OC subtypes, the mechanisms underlying OC malignancy and metastasis remain largely unknown. Ovarian clear cell carcinoma (OCCC) accounts for 5-25% of OC and its incidence rate is rising. Liver metastasis is particularly high in OCCC patients and leads to significantly reduced median survival. Why OCCC metastasizes to liver at such high frequency remains elusive. We previously identified MEX3A as a key factor that promotes OCCC tumorigenesis in part […]
- by Ramarao-Milne, P., Kaphle, A., Reguant, R., Klein, A., Kuiper, M., Hosking, B., Wenzel, J., Al-Mamun, H., Elazab, L., Zhong, Q., Reddel, R., Wilson, L., Jain, Y., Twine, N., Bauer, D.Background: Resistance to targeted molecular therapies, both primary and acquired, remains a major obstacle to effective cancer treatment. Despite extensive research, the molecular determinants of treatment resistance are still incompletely understood, underscoring the need to identify robust resistance drivers to improve therapeutic outcomes. Recently, the ProCan and Wellcome Sanger Institute released the largest pan-cancer proteomic dataset to date, comprising 949 cancer cell lines treated with 625 anticancer agents. Despite progress in identifying single protein markers, scalable methods for detecting synergistic […]
- by Bakin, A. V., Alruwaili, M., Guo, Y., Zonneville, J., Melendy, T., Straubinger, R. M., Foster, B. A., Rajan, P., Withers, H., Chatley, S., Iyer, R., Fountzilas, C.The tumor suppressor TP53 gene (p53) is mutated in most human malignancies but existing treatment options are largely ineffective, lack selectivity, and cause toxic side effects. To address these clinical problems, we have developed a two-drug treatment that induces lethal DNA damage and G2-arrest in p53 mutant cancer cells. Here, we present a triple-drug therapeutic strategy that combines our two-drug regimen with a G2-checkpoint kinase inhibitor. The two-drug treatment with TAS102 plus PARP inhibitor (PARPi) acts as an inducer-amplifier pair […]
- by POLL, A. A., Shi, Y., Rauwolf, K. K., Bornhauser, B., Kulozik, A., Bourquin, J.-P., Irving, J. A., van Delft, F.Children with T-cell acute lymphoblastic leukaemia (T-ALL) who relapse or fail induction have poor outcomes. A subset of cases show glucocorticoid resistance reversible by dasatinib through inhibition of LCK-dependent signalling. To identify a practical biomarker of dasatinib response, we compared in-vitro drug sensitivity with basal phosphorylation of pre-TCR pathway proteins in 28 paediatric T-ALL patient-derived xenografts (PDX). Phospho-flow cytometry quantified LCK (pY394), ZAP70 (pY319) and CD3{zeta} (pY142), normalised to internal controls. Dasatinib IC values correlated significantly with pLCK and pZAP70, […]
- by Cisneros, L. H., Toruner, M. D., siddiqui, Z., Maraone, A. V., Lin, M., Xiao, A., Thiels, C., Truty, M. J., George, B., Jazieh, K., McWilliams, R., Maley, C. C., Hartley, C., Elhalaby, R., Dizona, P., Shi, Q., Fernandez-Zapico, M. E., Carr, R. M.Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after total neoadjuvant therapy (TNT) and curative-intent resection. Traditional histopathologic response assessments demonstrate that major pathologic response (
- by Shahid, S. A., Al-Harrasi, A., Alsiyabi, A.Early and accurate diagnosis of prostate cancer (PRC) remains a major clinical challenge, particularly with existing biomarker panels relying on invasive sampling or large biomarker panels with limited interpretability. Here, we present a machine learning framework for discovering compact and biologically grounded plasma protein signatures for PRC classification using publicly available pan-cancer proteomic data. We coupled a genetic algorithm-based protein identification method with LASSO-regularized logistic regression to identify minimal protein subsets optimized for diagnostic performance. A 14-protein panel, recurrent across […]
- by Venkataramani, P., Elkayam, E., Garg, A., Cheng, K. F., Altiti, A., He, M., Thakur, K., Michalopoulou, E., Gonzalez, C., Van Aelst, L., Pappin, D., Joshua-Tor, L., Al-Abed, Y., Tonks, N. K.Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) is crucial for normal brain development and its disruption has been linked to various cancers. DYRK1A drives glioblastoma (GBM) progression via stabilization of epidermal growth factor receptor (EGFR). Here we describe two, selective, benzothiazole-derived DYRK inhibitors, FC-2 and FC-3, obtained by structure-activity optimization of a natural product lead. Both compounds inhibit DYRK1A with nanomolar potency and display high selectivity across a kinase panel. The co-crystal structure of FC-3 with DYRK1A revealed ATP-competitive binding, with interactions […]
- by Lempiainen, J. K., Miachin, K., Liu, X., Yang, K., Horth, C., Bareke, E., Grinwald, M. F., Saintilnord, W. N., Wang, T., Majewski, J., Hirbe, A. C., Garcia, B. A.Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with limited therapeutic options. Loss of the Polycomb repressive complex 2 (PRC2), via inactivating mutations in SUZ12 or EED, occurs frequently in MPNSTs and is associated with poor prognosis. However, the downstream chromatin and signaling consequences of these mutations remain incompletely understood. Here, we show that PRC2 deficiency in MPNST cells induces coordinated chromatin remodeling, characterized by loss of repressive H3K27me3 and gain of activating marks, including H3K27ac and H3K36me2. Integrative […]
- by Jain, C., Essani, M., Kumar, R., Das, N. k., Singhal, R., Rossiter, N. J., Chen, B., Huang, W., Lee, Z. H., Solanki, S., Zhang, Y., Sajjakulnukit, P., Zhang, L., Dalal, P. J., Hanna, D. A., McCollum, S., Stoffel, E. M., Greenson, J. K., Maher, L. J., Lyssiotis, C. A., Banerjee, R., Shah, Y. M.Colorectal cancer (CRC) cells are addicted to iron, which fuels nucleotide synthesis, mitochondrial respiration, and rapid proliferation. Yet paradoxically, high intracellular iron is cytotoxic to most other cells, raising the question of how CRC cells tolerate and exploit iron-rich environments. One pathway thought to mediate iron toxicity is ferroptosis, an iron-dependent form of cell death. However, most ferroptosis regulators were identified through synthetic chemical screens or small molecule activators, and it remains unclear whether these canonical pathways explain how iron […]
- by Wang, Y., Chen, S., Wu, Y., Cao, Y., Shi, Z., Norinskiy, M. A., Wang, C., Celik, H., Zhang, Z.The RAS oncogenes (KRAS, HRAS, NRAS) are among the most frequently mutated genes in human cancer, affecting over three million patients annually. Therapeutic development has largely focused on inhibitors for KRAS codon 12 mutations (G12C/D/V/S/R) which are key drivers in lung, colorectal, and pancreatic cancers. In contrast, mutant-selective inhibitors for Q61 variants remain elusive. A common mechanistic feature of G12 and Q61 mutants is the impaired hydrolysis of GTP, which traps Ras in its active, signaling-competent state. We envisioned that […]
- by Li, X., Xu, S., Peng, Y., Su, Z., Wang, S., Li, A., Huang, X., Shao, Z., Du, Y.Osteosarcoma is the most common primary malignant bone tumor in adolescents. Despite significant progress in multimodal therapies, its clinical efficacy remains severely limited by chemotherapy resistance. To overcome the barriers of DNA repair and drug efflux associated with resistance, we developed a biomimetic nanoplatform with cascade targeting capability, termed TAT-mPDO@cRGD-M. This system employs a polydopamine (mPDA) core with strong photothermal conversion and drug-loading capacity to co-deliver cisplatin and the PARP inhibitor olaparib. The surface is functionalized with a nuclear localization […]
- by Chatterjee, S., Jaiswal, R., Roy, A., Chowdhury, S., Mukherjee, S., Chowdhury, R.Colorectal cancer (CRC) is one of the deadliest cancers, ranking third in cancer incidence worldwide. These tumor cells often adopt unique strategies under drug stress to attain a reversible drug-tolerant state and evade cell death. However, the molecular adaptations associated with this transitory emergence of the drug-tolerant state remain elusive. Herein, epigenetic alterations often dictate such reversible dynamic changes, and this study aims to characterize the role of specific epigenetic modifiers governing CRC cell survival under drug pressure and their […]
- by Monaghan, J., Woytowich, N., Zhao, T., Nguyen, K., Mahony, E., Lum, J. J., Duncan, K. D.Mass spectrometry imaging (MSI) is emerging as a powerful tool for uncovering the distribution of metabolites in the tumor microenvironment and studying tumor metabolism in vivo. However, to date, MSI of primary patient biobanked tissues contextualized by patient data has been limited to peptides, proteins, and glycans – with few examples for metabolites. This is because most biobanked fresh-frozen tissue required for spatial metabolomics is embedded in optimal cutting temperature compound (OCT), which introduces high-abundance polymeric interferents. Herein, we use […]
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