- by Villaume, M. T., Ramsey, H. E., Impedovo, V., Davidson, M., Arrate, M. P., Singh, A. K., Lee, Y., Skwarska, A., Almadani, Y. F., Baran, N., Chaudhry, S., Reisman, B. J., TenBarge, E. G., Jiang, M., Monteith, A. J., Olmstead, S., Gorska, A. E., Zhao, Z., Grace, P. M., Bachmann, B. O., Konopleva, M., Tiziani, S., Savona, M. R.Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to […]
- by Warner, M. A., Sargent, J. K., Farley, S. R., Dumont, B. L., Hasham, M. G.Genetic uniqueness of the tumor microenvironment significantly influences cancer growth, survival, and response to therapy, independent of the cancer cell's intrinsic properties or the adaptive immune system. Using genetically distinct Rag1-/- mouse models, this study shows that different strains exhibit varied tumor growth kinetics and survival outcomes when xenografted with identical leukemic and solid tumor cell lines. This study further highlights the critical role of the myeloid immune compartment and shows that disrupting both lymphoid and myeloid systems alters cancer […]
- by Liang, W., Falk, L., Lucarelli, D., Putze, P., Metwaly, A., Zheng, Y., Springer, F., Winogrodzki, T., Chan, Q., Zhang, Y., Zeller, G., Meier, M., Schnieke, A., Ebner, F., Haller, D., Flisikowska, T., Saur, D., Flisikowski, K.Several inherited predispositions to colorectal cancer exist, most notably familial adenomatous polyposis (FAP), which typically involves a germline loss-of-function mutation in one APC allele. A second hit in APC or related loci leads to aberrant Wnt signalling, triggering adenoma formation with near-complete penetrance. Yet, substantial variability in disease onset and severity, even among siblings with identical APC germline mutations, implicates environmental modifiers. Emerging evidence points to the gut microbiome as a critical regulator of adenoma initiation and progression, particularly in […]
- by Hockaden, N., OHerron, E., Zhou, D., Heffernan, M., Cooper, S., Richardson, A.Background/ObjectivesGlioblastoma is an aggressive primary brain tumor that develops within a chronically low-oxygen microenvironment, yet most preclinical studies are performed under atmospheric oxygen conditions that poorly reflect in vivo physiology. This study investigated how sustained culture under physiological oxygen tension (physioxia; 5% O{square}) influences glioblastoma cell behavior, signaling, and therapeutic response. MethodsMultiple patient-derived glioblastoma models were cultured under normoxia (21% O{square}) or sustained physioxia (5% O{square}) for at least seven days before experimentation. Cell migration, proliferation, cell cycle distribution, expression […]
- by Troumpoukis, D., Papadimitropoulou, A., Charalampous, C., Kogionou, P., Polissidis, A., Nicolaides, N., Koutmani, Y., Serafimidis, I.Pancreatic cancer (PC) exhibits a striking association with depression, with neuropsychiatric symptoms frequently preceding diagnosis. However, the biological mechanisms linking pancreatic tumor development to central nervous system dysfunction remain poorly understood. Here, we investigated the impact of PC progression on adult hippocampal neurogenesis using complementary orthotopic xenograft and genetically engineered mouse models. Tumor-bearing mice developed depressive-like behavioral abnormalities accompanied by reduced adult hippocampal neurogenesis, including depletion of neural stem cell populations and immature neurons in both dorsal and ventral dentate […]
- by Mou, H., Yakovishina, V., DeRosa, K., Chen, Y., Xiao, M., Dunne, M., Shi, N., Thomas, M., Smith, J. L., Liu, Q., Herlyn, M.Combination targeted therapy with BRAF/MEK inhibitors and immune therapy show promising therapeutic outcomes in melanoma; however, the development of drug resistance still represents a formidable challenge. Remaining unexplored is the possibility that BRAF/MEK inhibitors themselves inadvertently compromise the tumor immune microenvironment, limiting the efficacy of immunotherapy when it is used in combination with targeted inhibitors. Herein, we profiled the landscape of the BRAF regulatome identifying a novel transcription factor, TFAP2A, newly linking BRAF/MEK drug resistance to antitumor immunity. Specifically, we […]
- by Wendt, J. R., Adams, K. M., Moreno, R., Hossan, M. S., Stram, A., Lin, E. S., Kersten, L., Kratz, J. D., Roy, M., McGregor, S. M., Lang, J. D.Patient-derived organoids (PDOs) have transformed translational cancer research, allowing tractable models that better represent clinical features than traditional immortalized cell lines. Here we describe two PDOs with differential responses to carboplatin derived from sequential ascites fluid collections from a patient with high-grade mullerian carcinoma, that could not be further subclassified on the omental biopsy. Uterine origin was clinically excluded by pelvic imaging/CT scan of the uterus and absence of vaginal bleeding. Successful derivation from independent collections enabled comparison of intra-patient […]
- by Yesudhas, D., Lone, B., Unal, E., Chakraborty, A., Keskus, A. G., Ryou, J., Butler, K., Aquino, T. C., Yousefi-Rad, A., Yang, W., Jenkins, L. M., Chelluri, R., Chandran, E. B., Romero, V. A. V., Boudjadi, S., Gurram, S., Kolmogorov, M., Apolo, A. B., Banday, A. R.Hypermutational processes, including those driven by the APOBEC3 family of cytidine deaminases, generate abundant neoantigens yet give rise to tumors that evade immune recognition. Here, using multi-omics analyses followed by functional validation, we identified a tumor-intrinsic immune-cloaking mechanism in neoantigen-rich epithelial cancers, characterized by coordinated suppression of antigen presentation, immune-recruiting cytokines and immune-checkpoint programs. In bladder cancer, genome-wide copy-number analysis identified recurrent 1q23.3 amplification as a genomic feature of a neoantigen-high/CD8-low tumor state. Within this locus, NECTIN4 emerged as the […]
- by Dhingra, L., Singh, M., Jit, S., Yadav, D., Bhalla, S.Triple-negative breast cancer (TNBC) exhibits pronounced molecular heterogeneity, yet the majority of published transcriptomic prognostic signatures suffer from limited reproducibility and have not achieved clinical translation. We systematically benchmarked 62 published TNBC prognostic signatures across 6 independent cohorts (n=1,357) using a unified analytical framework spanning multiple scoring algorithms, survival endpoints, and threshold strategies. While 17 signatures demonstrated consistent univariate prognostic associations, only 4 remained independently prognostic after adjustment for clinicopathological variables, and none achieved robustness across all analytical conditions-underscoring the […]
- by Chen, J. Y., Saghapour, E., Kurmachalam, N., Oishe, G., Sembay, Z.Pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic KRAS in roughly 90% of cases, and KRAS-pathway inhibition has finally become clinically active. Durable benefit, however, will require identifying the adaptive and baseline vulnerabilities that shape response to KRAS inhibition. Two resistance mechanisms have been proposed separately in the literature – receptor-tyrosine-kinase bypass of KRAS, and dependence on the adhesion kinase FAK – but whether they are one target class or two, and which should partner a KRAS inhibitor, is unresolved. […]
- by Li, J., Zhu, Z., Zheng, E., Xiong, J., Liu, A., Hu, T., Ma, Z., Liu, C.Multicellularity is a well-documented microbial response to stress, however its role as an adaptive survival strategy in cancer remains unresolved. Here we reveal that drug stress, such as paclitaxel treatment, enable rapidly (within 24-48 hours) and efficiently (~20-40%) convert single mouse breast 4T1 cancer cells into clonal multicellular spheroids, ultimately generating multicellular masses. Notably, multicellularity is reversible: upon stress removal, most of them restore a unicellular lifestyle that quickly becomes dominant. This transient multicellular state shields cells from hostile niches, […]
- by Mandzhieva, B., Verma, A., Nguyen, T. D. T., Bang, Y. H., Park, W. Y.Fibroblast heterogeneity shapes tumor progression, yet the transitional states linking normal-associated fibroblasts to cancer-associated fibroblasts (CAFs) remain poorly defined. Here, we integrated single-cell transcriptomic profiles of more than 90,000 stromal cells from 281 samples across nine cancer types to construct a pan-cancer atlas of fibroblast diversity. We identified a distinct CAF-like population positioned between normal-activated fibroblasts and established CAF subsets along the inferred fibroblast activation trajectory. Integration with single-nucleus chromatin accessibility data identified FOXF1 and FOXF2 as candidate regulators of […]
- by Dorbin, D., Herrera, J., Davidson, R., Chandrashekar, N. K., Scheuber, G., Jayakrishnan, P., Rajesh, C., Johnson, G., Yuan, J., Sochor, M., Langenheim, J. F., Aldakkak, M., Messerly, C., Wittmann, J., Szabo, A., Sayahpour, F. A., Atallah, N. L., Peterson, F. C., Volkman, B. F., Ali, M., Ke, E., Evans, D. B., Tsai, S., Lytle, N. K., Seo, Y. D., Kurzrock, R., Hobbs, G. A., Kamgar, M., McFall, T.Clinical-grade RAS inhibitors raise an unresolved question: do oncogenic KRAS-alleles impose distinct constraints on adaptive resistance that can be exploited therapeutically? Using daraxonrasib (RMC-6236), a multi-selective RAS(ON) inhibitor, we compared resistance mechanisms between KRASG12D and KRASG12R, alleles with fundamentally different RAS network dynamics. Daraxonrasib inhibited KRASMUT primarily through steric occlusion of effector binding, while engaging RASWT only modestly (~20%) via accelerated GTP hydrolysis. KRASG12R is marked by its inability to transactivate RASWT, and it was observed that daraxonrasib resistant KRASG12R […]
- by Dahiya, R., van Belzen, I. A. E. M., Liao, C., Kumar, A., Lin, Y.-F., Ko, A., Mennie, A. K., Aleksandrovic, E., Zhou, J., Hu, Q., Engel, J. L., Miyata, J., Espejo Valle-Inclan, J., Rust, A. G., Maddipati, R., Brugarolas, J., Malladi, S., Zhang, S., Kapur, P., Zhang, Q., Cortes-Ciriano, I., Ly, P.Clear cell renal cell carcinoma (ccRCC) is initiated by chromosome 3p loss, yet chromosome losses impose a profound fitness burden on normal cells. How renal epithelial cells tolerate this deleterious aneuploidy during early tumorigenesis remains unclear. Analysis of 949 ccRCC genomes reveals two major classes of chromosome 3p alterations: simple deletions and complex rearrangements surrounding a terminal breakpoint – a pattern we term breakpoint-confined chromothripsis. We modeled both alterations in non-transformed human renal proximal tubule epithelial cells by introducing a […]
- by Duan, X., Lu, Y., Zhou, H., Zhang, Z., Zhou, Z., Wang, M., Dun, X., Chen, Z., Zhu, Y., Wang, H., Jiang, L.Chemotherapy treatment of colorectal cancers (CRC) using cisplatin (CDDP) encounters problems of drug resistance by the cancer cells and cytotoxicity to normal cells, highlighting the urgent need for joint therapeutical strategies. Selenium-enriched rapeseed extracts exhibit anti-cancer effects but the bioactive components and mechanisms remain unclear. Here, we applied different solvents to fractionate the extracts from Selenium-enriched rapeseed and found that the water extract (WE) fraction significantly enhanced the cytotoxic effect of CDDP on cancer cells but no damage on normal […]
- by Baker, C., Ren, T., Rafferty, K., Wang, H., McDade, S.The acceleration of automated scientific discovery has been fundamentally bottlenecked by the epistemic gap between the semantic reasoning of large language models (LLMs) and the complex, non-linear reality of mammalian biology. While recent multi-agent frameworks have achieved autonomous hypothesis generation and in vitro experimental analysis, they frequently lack the rigorous statistical constraints required for multi-scale clinical translation. Furthermore, while algorithmic clinical digital twins successfully forecast biological states, they often rely on opaque latent spaces, sacrificing mechanistic interpretability for predictive accuracy. […]
- by Iden, M., Schmidt, R., Mohammed, R. D. A. S., Dlugi, T. A., Kumar, R., Tsaih, S.-W., Nosirov, B., Kadamberi, I. P., Mittal, S., Narayan, S. L., Bradley, W. H., Erickson, B., Czaja, R. C., Felix, J. C., Jin, V., Ojesina, A. I., Pradeep, S., Smith, B. C., Rader, J. S.TAOK3 is a lesser-studied MAPK family serine/threonine kinase our group has shown to be targeted by HPV integration, suggesting a potential role in driving invasive cervical cancer (ICC). Here, we profiled TAOK3 expression in patient tumors, metastases, and cervical cancer models and localized TAOK3 within a tumor epithelial subpopulation by integrating two single-cell RNA-seq datasets. Functional consequences of TAOK3 loss were assessed with siRNA and CRISPRi in cell lines and 3D spheroids. In vivo effects were evaluated in intracervical xenografts […]
- by Ng, S. W., Gadde, S., Chung, N.-y., Wang, Q., Doughty, L., Nero, T. L., Jayatilleke, N., Seneviratne, J., Carter, D. R., Mateos, M. K., Tsoli, M., Ziegler, D. S., Endersby, R., Kumar, N., Chesler, L., Liu, T., Parker, M. W., Cheung, B. B., Marshall, G. M.Background: Medulloblastoma (MB) is the most common malignant brain tumour in children, and aggressive subgroups are frequently driven by the oncoproteins MYC or MYCN. Direct therapeutic targeting of MYC/MYCN has been challenging because of their intrinsically disordered protein structures. The aim of this study was to determine whether novel SE486-11 analogues (UNSW-SCs) can therapeutically target MYC/MYCN-driven MB. Methods: The anticancer activity of UNSW-SCs was assessed in MB cell lines with differential MYC/MYCN expression. Target engagement was evaluated using surface plasmon […]
- by Jesus-Ferreira, H. C., Teodoro, L., Carreira, A. C. O., Sogayar, M. C.Long non-coding RNAs (lncRNAs) have attracted increasing interest because of their roles as modulators of tumor progression, acting either as oncogenic drivers or tumor suppressors, depending on the cellular context. LINC01133 has been implicated in regulation of multiple tumor-related mechanisms; however, its role in breast cancer, particularly in the triple-negative subtype, remains poorly characterized. In this study, we investigated the impact of LINC01133 depletion on malignant phenotypes and on the expression of migration- and invasion-associated genes using the Hs578T triple-negative […]
- by Ong, K. L., Cajulao, J. B., Anders, K. M., Bilder, D.Tumors exploit wound healing pathways not only to foster progression but also to lethally disrupt systemic physiology. A prominent example is malignant activation of the clotting cascade, causing pathology through unclear mechanisms that extend beyond thrombosis. Here we show that tumors in a coagulopathy-inducing Drosophila cancer model remotely disrupt intestinal stem cell (ISC) homeostasis. This paraneoplastic, tumor-gut communication axis induces intestinal dysplasia and barrier dysfunction, mimicking remote chronic injury that we show activates inflammation in ISCs via EGFR signaling. Unlike […]
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