- by Abdelmageed, A. A., Smerczynski, J., Kandwal, M., Douglas, L., Russell, T., Morris, M., Dewhurst, S., Ferran, M.Cancer cells often have defects in antiviral pathways, making them susceptible to oncolytic viruses like vesicular stomatitis virus (VSV). However, some cancer cells resist viral infection through the constitutive expression of interferon-stimulated genes. This study examined whether NF{kappa}B activation and NF{kappa}B dependent antiviral signaling contributes to resistance to VSV infection in the PC3 cell line, derived from an aggressive metastatic prostate cancer (PrCa) tumor. We found that NF{kappa}B localized to the nucleus in VSV-infected PC3 cells, but not in the […]
- by Plaisier, S., Phavong, R., Farmwald, M., Lee, M., Allen, T., Swamy, M., Rodriguez, I., Wells, M., Phaneuf, N., Massey, S. C., Del Rosario, J., Hart, J., Mangelsdorf, A., Van Der Jagt, M., DeCasien, A. R., Buetow, K. H., Wilson, M. A.Although there are known sex differences in cancer incidence, severity, and treatment, the sex chromosomes are typically excluded from genomic analyses because of the unique technical challenges associated with assessing their copy number, sequence variation, and expression. Here we assess sex chromosome complement in three widely-used human genomics datasets from normal (non-cancerous) tissues, primary tumors, and cancer cell lines and study the effects on genome-wide gene expression. Expected sex chromosome complements based on reported patient sex were observed in non-cancerous […]
- by Apitikori-Owumi, J. E., Sonibare, M. A., Nwankwo, L. U., Nweke, S. C., Akpomadaye, E. C., Firdous, S. M.Background: Chrysobalanus icaco L. (Chrysobalanaceae) is a spice commonly used by the Ijaws, Itsekiris, and Urhobos in Delta State. In ethnomedicine, it helps treat conditions such as diarrhoea, diabetes, high cholesterol, infections, and inflammation. Objective: The study evaluated the growth inhibitory effect of C. icaco seed and its chromatographic fractions. Method: The powdered seed sample of C. icaco was extracted with 70% ethanol by cold maceration, and the extract was screened for the presence of secondary metabolites. The extract was […]
- by Ritting, M. L., Yang, W., Aalam, S. M. M., Zhao, H., Feng, L., Song, J., Dumbrava, M., Ismail, W. M., Mun, D.-G., Hu, C., Roy, O., Chaludiya, K., Shi, G. X., Crasta, D. N., Schaufelberger, K., Janus, J. R., Kalthur, G., Weroha, S. J., Kaufmann, S., Sadanandam, A., Knapp, D. J., Wang, C., Pandey, A., Gaspar-Maia, A., Couch, F. J., Sherman, M. E., Bakkum-Gamez, J. N., Kannan, N.To illuminate the origins of high-grade serous ovarian cancer (HGSOC), the most lethal and common form of ovarian cancer, we have created a comprehensive living organoid biobank of human fallopian tube tissue, which is thought to be the origin of this cancer. Through optimized culture protocols and integrated multiomic profiling including single-cell RNA sequencing, chromatin accessibility (ATAC) analysis, proteomics, and secretomics we assembled the largest molecular atlas of the fallopian tube epithelium to date. This resource revealed diverse epithelial lineages […]
- by Parsons, T. M., Krishnan, A., Xavier Raj, I., Young, A. L., O'Leary, D. R., Arand, J., Cox, M., Oh, S. T., Challen, G. A.Myeloproliferative neoplasms (MPNs) are hematological diseases predominantly driven by the JAK2V617F mutation. Progression from chronic-phase MPN to secondary acute myeloid leukemia (sAML) is a severe complication that dramatically worsens disease prognosis. While progression to sAML is classically linked to MPN clones acquiring additional mutations, the absence of JAK2V617F in some cases of post-MPN sAML cases suggests alternative mechanisms of transformation. Utilizing patient samples and in vivo modeling, we establish that leukemic clones can emerge independently of JAK2-mutant cells and undergo […]
- by Madigan, J. P., Andrews, S. G., Farrell, R. B., Sharma, R., Ceribelli, M., Thomas, C. J., Shamsian, K. N., Lin, S., Cheng, K. C.-C., Sadowski, S. M.Pancreatic neuroendocrine tumors (PNETs) are a rare and understudied set of cancers, with increasing incidence. Neuroendocrine tumors are unique in the fact that they express high levels of the somatostatin receptor type 2 (SSTR2), which represents a target for both tumor imaging and therapeutics. PNET grade inversely correlates with SSTR2 tumor staining and higher tumor grade is associated with poor patient prognosis. With no known mutations, SSTR2 expression is believed to be lost through aberrant epigenetic mechanisms. Enhanced knowledge of […]
- by Kopp, L. L., Ciraulo, B., Hochuli, D., Versamento, D., Baumgartner, M.The scaffold protein FRS2 is central to FGFR signaling, linking receptor activation to MAPK/ERK and PI3K/AKT pathways. Elevated FRS2 expression correlates with aggressive tumor phenotypes and poor prognosis across multiple cancers, including medulloblastoma (MB). Here, we characterized FRS2's subcellular localization and interactome in MB cells, employing live-cell imaging, phosphoproteomics, immunoprecipitation, and APEX2-based proximity labeling. This study demonstrates that increased motile and invasive behavior in MB tumor cells is associated with increased FRS2 expression. We identified novel FRS2-associated proteins involved in […]
- Colorectal cancer-associated PCBP1 mutations disrupt protein stability in a dominant negative mannerby Blinkiewicz, P. V., Hoenes, N. C., Afzal, M. X., Liu, Y., Hill, U. J., Bjarnadottir, B., Burgin, T. E., Malaney, P.Mutations in RNA-binding proteins are increasingly identified in cancers through tumor sequencing and are correlated with disease progression, therapy response, and overall patient outcomes, underscoring the need to study them. Here, we focus on the RNA-binding protein Poly-C binding protein 1 (PCBP1), which binds target RNAs through K-homology (KH) domains to regulate RNA fate. PCBP1 is a tumor suppressor gene and hotspot missense mutations at leucine residues 100 and 102 are observed in colorectal cancer (CRC). PCBP1 mutations have been […]
- by Goldman, A., Gonzalez, G., Karpova, S., Buon, L., SHAMMAS, M. A., Mashimo, H., Frank, M., Frank, N.Background: Esophageal adenocarcinoma (EAC) frequently arises from chronic exposure to acid and bile reflux, with secondary bile acids, such as deoxycholic acid (DCA), contributing to its pathogenesis through mechanisms involving reactive oxygen species (ROS), oxidative DNA damage, and resistance to apoptosis. The human endocannabinoid system (ECS) regulates diverse anti-inflammatory, antioxidant, and analgesic pathways implicated in disease modulation. Despite its therapeutic promise, effective pharmacological activation of the ECS remains challenging. Objectives: This study aimed to evaluate whether specific cannabinoid-terpene combinations targeting […]
- by khamari, A., Guria, A., Tak, K., Sharma, R., Kalaidzidis, Y., Datta, S.Metastasis is one of the primary causes of cancer-related death in TNBC patients. During metastasis, stromal infiltration requires the cancer cells to form invadopodia, a membraneprotrusion with proteolytic activity. Cues from growth factors via the cognate RTKs promote invadopodia formation and cancer cell invasion. This study demonstrated the role of the HGFMET axis in invadopodia formation and associated protease trafficking. MET interacts with MT1-MMP and is co-transported to the cell surface. Further, the RTK is found to reside at invadopodia, […]
- by Oza, V. D., Williams, C., Blackburn, J. S.The Genetically Encoded Death Indicator (GEDI) is a ratiometric, dual-fluorescence biosensor that enables real-time detection of cell death through calcium influx. Originally developed for use in neurodegeneration models, GEDI can be applied to cancer cells to quantify therapy-induced death at single-cell resolution. This protocol details how to generate GEDI-expressing cancer cell lines, empirically determine stress-induced GEDI thresholds using radiation or chemotherapeutic agents, and perform time-resolved imaging and image analysis to track cell fate. This workflow is optimized for high-throughput drug […]
- by Wang, Q., Li, L., You, L., Wang, S., Han, L., Wang, B., Yao, L., Lu, Y., Mender, I., Flusche, A. M., Kim, C., Yarravarapu, N., Lemoff, A., Lum, L., Shay, J. W., Yu, Y., Chen, C.Aberrant WNT/{beta}-catenin signaling drives tumorigenesis and metastasis in cancer. Although enzymatic inhibitors of tankyrase (TNKS) effectively block AXIN degradation and stabilize the {beta}-catenin destruction complex (DC), they have demonstrated limited efficacy in various cancer models. Here we demonstrate that, unexpectedly, the induction of AXIN puncta represents a major barrier to achieving therapeutic efficacy. Mechanistically, catalytic inhibition of TNKS prevents TNKS turnover and drives its accumulation in the DC, wherein the scaffolding function of TNKS induces AXIN puncta formation, rigidifies the […]
- by Bhole, G., HC, P., Jayachandran, M., PK, V., Bhimalapuram, P.Accurate molecular subtyping of cancer is crucial for advancing personalized medicine. Although multiomics data contain valuable predictive information, effectively integrating them is challenging due to differences across modalities, high dimensionality, and complex cross modal biological interactions. We propose HyperCLSA (Hypergraph Contrastive Learning with Self-Attention), a novel deep learning framework for efficient multi-omics integration in breast cancer subtyping. HyperCLSA combines hypergraph-based sample encoding, supervised contrastive learning for latent space alignment, and multi-head self-attention for adaptive fusion of omics modalities. Evaluated on […]
- by Emon, B., Kashefi, A., Rahman, M. H., Adnan, D., Ospina-Munoz, N., Mellican, S., Santiago, S., Drennan, W. C., Joy, M. S. H., Phan, A. A., Afrin, T., Han, B., Smith, K. C., Bishehsari, F., Saif, M. T. A.The tumor microenvironment plays a critical role in drug resistance, with extracellular matrix (ECM) mechanics, cell-cell crosstalk, and transport barriers contributing to poor therapeutic outcomes. Traditional two-dimensional (2D) cultures fail to capture these features, and drug efficacy in 2D often does not translate to three-dimensional (3D) models or in vivo tumors. Here, we introduce a 3D tumor model integrated with a high-throughput biomechanical sensor array that enables simultaneous measurement of cellular forces, matrix remodeling, and molecular transport. Fabricated using a […]
- by Wang, Y., Baluapuri, A., Manokaran, C., Ni, J., Jiang, T., Janssens, R., Marteijn, J., Adelman, K., Zhao, J., Roberts, T.The process of transcription is driven forward by the activity of kinases including CDK7, CDK9 and CDK12. Accordingly, acute inhibition of any of these kinases results in profound downregulation of gene expression. Here, we discover that loss or inhibition of CDK12 also significantly upregulates a set of coding and non-coding loci, whose activation could contribute to the anti-proliferative effects of CDK12 inhibitors. Mechanistically, CDK12 inhibition impairs transcription elongation, leading to increased RNA polymerase II termination or arrest in long genes. […]
- by Zok, S., Linial, M.Long non-coding RNAs (lncRNAs) are key regulators of gene expression, chromatin remodeling, and signaling. Recent estimates suggest that the human genome contains more than 35,000 lncRNA genes, with roughly 20% predicted to encode micropeptides (MPs) with unknown functions. In this study, we focused on the subset of lncRNAs with strong statistical evidence for MP-encoding potential, accounting for approximately 8% of the unfiltered MPs collection. Our analysis centered on 1,782 high-confidence lncRNA-MPs derived from 478 genes expressed across 17 cancer types […]
- by Ghosh, P. K., Das, S., SN, G. G., Ghosh, S., Maitra, A., Das, M., Das, S.Retinoblastoma gene (RB1) mutation has been reported in lung cancer, retinoblastoma and cervical cancer etc. Here, we elucidate the involvement of RB1 mutations and their regulation in endometrial cancer. Analysis of mutation data of 547 endometrial cancer samples revealed that 12% of samples harboured RB1 mutations. However, 26% of the patients aged between 30 and 50 years harboured RB1 mutations, compared to only 10% in the older age group. Further, in silico interaction studies and structural analysis of these novel […]
- by Mogol, A. N., Yoo, J. Y., Eve, A. A., Goel, M., Dutton, D. J., Schane, C. P., Lam, A., Dutta, D., Barnick, B., Erdogan, E. D., Nelson, E. R., Grosse-Perdekamp, M., Madak-Erdogan, Z.Endocrine therapies target hormone-dependent cancer cells, primarily through estrogen receptor alpha (ERa), expressed in ~70% of breast cancers (ER+). Despite treatment advances, 30-40% of ER+ breast cancer patients experience recurrence and metastasis, with 5-year survival rates of only 31.9%. We validated poor outcomes for liver metastasis patients treated with Fulvestrant (Fulv) using the local Carle Foundation Hospital cohort and examined metabolic pathways in liver metastatic patient-derived xenograft (PDX) models, revealing upregulated lipid and acetyl-CoA production. Our previous work demonstrated that […]
- by Lin-Rahardja, K., Canavan, E., Scott, J. G.Therapeutic options for patients with relapsed or refractory Ewings sarcoma (EWS) remain limited. Collateral sensitivity, where resistance to one drug confers sensitivity to another, could be leveraged to optimize chemotherapy for EWS. Gene expression signatures that predict collateral sensitivity states can be used to guide treatment selection in an evolution-informed manner. We experimentally evolved resistance to first-line EWS chemotherapy in cell lines. Throughout, we measured collateral responses across a panel of anticancer drugs and quantified transcriptomic changes. Collateral drug responses […]
- by Haigis, K. M., Chen, J., Collins, R.Defining genes that are somatically mutated in different cancers is a central goal of cancer genetics. Nevertheless, traditional definitions of "driver" genes based on pooled mutation frequency are biased toward common cancer types and tend to overlook genes that might be specific to rarer subtypes. As such, our understanding of the compendium of cancer genes is incomplete. In this study, we developed a statistical framework that defines genes enriched for functional somatic mutations in primary cancers to quantify incidence and […]
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