- 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 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 Aoshima, K., Miyazaki, N., Goto, T., Heishima, K.Canine hemangiosarcoma (HSA) is an aggressive endothelial malignancy with limited therapeutic options, and its progression is closely associated with vascular architecture, stromal remodeling, and inflammatory cell recruitment. Sulfoquinovosylacylpropanediol (SQAP) is a sulfoquinovosyl lipid radiosensitizer reported to affect angiogenic and tumor-microenvironmental pathways, but its effects in canine HSA are unknown. Here, we evaluated SQAP in canine HSA cell lines and patient-derived xenograft (PDX) models. SQAP showed minimal direct cytotoxicity against HSA cell lines in vitro, whereas it significantly suppressed tumor growth […]
- 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 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 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 […]
- 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 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 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 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 Gopalakrishnan, A. S., Ariraman, S., Ganguli, S., Hitesh, A., Mohammad, S., B, M., Sudhakar, S., Chavali, P. L.Although anthracyclines such as epirubicin are potent DNA-damaging agents, their application in glioblastoma (GBM) is limited by poor intracellular penetration, lack of durable responses and rapid emergence of adaptive tumor phenotypes. Here, we demonstrate that nanoarchaeosome-mediated delivery of epirubicin (NanoEpi) enables functional reprogramming of GBM survival under therapeutic stress. Nanoarchaeosomes composed of archaeal ether lipids exhibited high encapsulation efficiency ([~]96%) and nanoscale stability. Although both Epi and NanoEpi showed similar bulk uptake, both in established (U251-MG) and patient-derived (Gli5) glioblastoma […]
- 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 Tandon, A., Nagalla, D.Microsatellite-stable/microsatellite instability-low colorectal cancer (MSS/MSI-L CRC) is generally resistant to immune checkpoint blockade, but the biological states underlying this resistance are heterogeneous. We integrated TCGA COAD/READ patient transcriptomic profiles, MSIsensor-based MSS/MSI-L classification, curated immune and stromal module scoring, focused differential expression and DepMap CRISPR dependency data to prioritize candidate vulnerabilities in immune-cold MSS CRC. Among 494 MSS/MSI-L tumours, 218 were classified as MSS intermediate, 102 as MSS immune-cold, 91 as MSS hot/inflamed and 83 as MSS barrier-high. MSS immune-cold tumours […]
- by Roggia, M., Chianese, U., Amendola, G., Albanese, V., Vetrei, C., Ierano, C., DAlterio, C., Di Maro, S., Ciardiello, F., Morgillo, F., Scala, S., Altucci, L., Preti, D., Schulte, G., Benedetti, R., Kozielewicz, P., Cosconati, S.Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense desmoplastic tumor microenvironment (TME) that limits drug penetration and promotes immune evasion. Effective treatment, therefore, requires simultaneous modulation of multiple signaling pathways. Here, we describe a directed polypharmacological strategy to identify dual modulators of c-MET and Smoothened (SMO), aiming to disrupt the protective stroma through SMO inhibition while directly suppressing tumor cell survival via c-MET targeting. An AI-guided virtual screening workflow combining the machine-learning platform PyRMD, trained on […]
- by Cumming, E. M., Rakovic, K., Pennel, K. A., Galbraith, L. A., Sandilands, E., Mitchell, L., McGarry, L., jackstadt, R., Gilroy, K., Nixon, C., Sansom, O. J., Le Quesne, J., Blyth, K., Edwards, J., Bryant, D. M.Glandular architecture – the coordination of lumen-containing structures by an apical-basal polarised epithelium – is frequently maintained in colorectal cancer (CRC), yet whether it actively contributes to tumour progression or metastatic competence remains unclear. Here, we identify Podocalyxin (PODXL), a developmental regulator of epithelial lumen formation, as a key determinant of glandular tumour architecture in CRC. PODXL is upregulated in CRC, particularly in poor-prognosis Consensus Molecular Subtype 4 (CMS4) tumours, where high expression predicts reduced survival. Using genetically engineered mouse […]
- by Amos, S. M., Chen, C.-C., Xiang, Y., Motoyama, K., Gonzalez-Robles, T., Narendra, V., Johnson, G., Lee, H. T., Ho, Y.-J., Celikoyar, I., Ye, Z., Guo, S., Glickman, C., O'Hearn, N., Sarkar, O., Arroyo-Ortega, A., Devine, T., Pagano, M. J., Ruggles, K., Sanchez-Rivera, F. J., Koehler, A. N., Lowe, S. W., Soto-Feliciano, Y. M.Chromatin regulation critically influences gene expression and cancer progression, yet the functions of chromatin adaptors remain incompletely defined. Using focused CRISPR screening, we identified TRIM28, a multi-domain chromatin adaptor, as a dependency in acute leukemia, where its depletion impaired leukemia cell proliferation in vitro and in vivo, while activating neutrophil differentiation programs. Integrative transcriptomic and chromatin profiling revealed that TRIM28 acts as a co-repressor of neutrophil-associated loci independently of H3K9 methylation, and that TRIM28 loss drives terminal differentiation of leukemia […]
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