- by Musick, M., Ufondu, C. A., Rowland, C. E., Sottnik, J. L., Shackleford, M. T., Nesiba, C. S., Ostrander, J. H., Sikora, M. J.Invasive lobular carcinoma (ILC) is a common subtype of breast cancer that is defined in part by genetic loss of CDH1 caused by mutation or deletion, leading to loss of cell adhesion protein E-cadherin in >90% of ILC. Genetic loss of CDH1 is an early event in ILC oncogenesis, yet the mechanisms by which CDH1/E-cadherin acts as a tumor suppressor are not well understood. To study how early CDH1 loss drives ILC oncogenesis, we used a series of non-transformed human […]
- by Jabeen, A., Awartani, D., Sherif, S., Ahmed, E. I., Alanany, R., Saleh, A., Hendrickx, W. R. L., Raynaud, C. M.Pediatric cancers pose significant treatment challenges due to their biological heterogeneity and variable responses to chemotherapy. SLFN11, a DNA/RNA helicase-like protein known to sensitize adult tumors to DNA-damaging agents, remains underexplored in pediatric malignancies. Here, we investigate the role of SLFN11 across pediatric Wilms tumor, osteosarcoma, and medulloblastoma using integrated bioinformatics, epigenetic profiling, and functional assays. In silico analysis of TARGET and ICGC datasets revealed distinct correlations between SLFN11 expression and patient survival, with positive, negative, or neutral predictive value […]
- by Akhshi, T., Hu, S. S., Wheeler, E., Hellriegel, C., Richardson, D. S., Cayting, N., Mvula, W., Ahmed, B., Jeselsohn, R., Zang, C., Brown, M.Changes in gene expression regulated by ligand-dependent transcription factors such as estrogen receptor- (ER) involves the recruitment of coactivators including p300 that acetylates histone H3 at lysine 27 (H3K27ac). While H3K27ac marks active enhancers, the detailed chromatin architecture of enhancers remains unclear. Using super-resolution microscopy, we reveal distinct structural states of H3K27ac modified chromatin in response to ER activation. In estradiol (E2)-treated cells, H3K27ac modified chromatin adopts open, elongated structures associated with active enhancers, while ER inhibition induces compact, spherical […]
- by Ayanlaja, A. A., Hong, X., Cheng, B., Han, Z., Chang, M., Kanwore, K., Adesanya, A. I., Ayanlaja, M., Raji, Q., Iqra, N., Alphayo-Kambey, P., Tang, C., Dong, J., Zhang, B.Gliomas are the most common primary intracranial tumors, comprising 81% of malignant brain tumors, and currently lack effective therapies. Recent advances in molecular biology have shown that cancer cells exploit microtubule-associated proteins (MAPs) under stress to activate various signaling pathways. This study investigates the role of Doublecortin (DCX) in glioma metabolism and its impact on tumor proliferation. In this study, CRISPR-engineered glioma models with DCX overexpression or knockdown were analyzed using integrated genomic, transcriptomic, and metabolomic approaches. Metabolic activity was […]
- by Ge, J., Hirosue, S., Patel, S. A., Wesolowski, L., Dyas, A., Yong, C., Castillon, L., de Haan, S., Drost, J., Stewart, G. D., Obenauf, A., Munoz-Espin, D., Vanharanta, S.The von Hippel-Lindau tumor suppressor (VHL) is a component of a ubiquitin ligase complex that normally controls cellular responses to hypoxia. Endogenous VHL is also utilized by proteolysis-targeting chimera (PROTAC) protein degraders, a promising class of anti-cancer agents. VHL is broadly essential for cell proliferation, yet it is a key tumor suppressor in renal cell carcinoma. To understand the functional consequences of VHL loss, and to identify targeted approaches for the elimination of VHL null cells, we have used genome-wide […]
- by Lee, H. M., Zheng, Z., Sorokin, A., Wong, C. W., Napolitano, S., Chowdhury, S., Kanikarla, P. M., Singh, A. K., Kochat, V., Bristow, C. A., Srinivasan, S., Peoples, M., Arslan, E., Alshenaifi, J. Y., Villarreal, O. E., Morris, V. K., Shen, J. P., Meric-Bernstam, F., Jain, A. K., Fowlkes, N. W., Anderson, A., Menter, D. G., Saw, A. K., Rai, K., Kopetz, S.BackgroundAberrant enhancer dynamics play a critical role in the initiation and progression of colorectal cancer (CRC). BRAFV600E-mutated metastatic CRC may be a unique subtype, exhibiting a strong epigenetic phenotype. Interestingly, bromodomain 2, a reader protein for H3K27ac-marked enhancers, was found to be synthetically lethal in CRC with BRAF + EGFR inhibition. DesignWe evaluated the effectiveness of targeting aberrant enhancers with bromodomain and extraterminal (BET) + MAPK pathway inhibitors in patient-derived xenograft models of metastatic CRC, followed by comprehensive profiling of […]
- by Kurstjens, E. M., Cox, K., Bali, P., Amirfakhri, S., Hernandez, J., Lozano-Pope, I., Benner, C., Bouvet, M., Obonyo, M.Helicobacter pylori (H. pylori) infection and consequent inflammation leads to gastric cancer (GC). Despite the prevalence of this bacterium and availability of genomic data, targeted therapies for GC are still early in development. Previously in our accelerated Helicobacter-induced gastric cancer mouse model we identified several differentially expressed genes (DEGs), including PSMB8 (proteasome subunit beta type 8, also called LMP7); one of the immune subunits of the immunoproteasome, which has been associated with disease severity in multiple cancers. We observed elevated […]
- by McGee, L. E., Grit, J. L., Essenburg, C. J., Agrusa, S., Turner, L., Becker, K., Dey, A., Klomp, J. E., Klomp, J. A., Adams, M., Beddows, I., Wolfrum, E., Fu, D., Hirbe, A. C., Graveel, C. R., Steensma, M. R.Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome caused by loss of function of the neurofibromin protein. Malignant peripheral nerve sheath tumors (MPNSTs) are a rare and deadly sarcoma with few therapeutic options that are the leading cause of death for patients with NF1. To date, no targeted therapies have been approved for MPNST treatment, highlighting the need for an understanding of adaptive signaling mechanisms that drive resistance. We developed a preclinical model of drug resistance using a cross-over […]
- by Lofgren, K. A., Feiszt, P., Kenny, P. A.Growth factor receptor-bound 7 (Grb7) is a multidomain adaptor protein implicated in signal transduction from multiple receptor tyrosine kinases, including ERBB2. ERBB2 amplification is a common event in breast cancer, and co-amplification of the neighboring GRB7 gene typically occurs, which has been presumed to lead to synergistic pro-tumorigenic signaling between both encoded proteins. Accordingly, GRB7 has been proposed as a candidate therapeutic target in breast cancer and other malignancies. Genetic deletion of Grb7 results in relatively phenotypically normal, viable, fertile […]
- by Dasari, S., Wang, J., Cheng, F., Melissa Halprin, M., Pepin, D., Yang-Hartwich, Y., Mitra, A. K.Extensive metastasis at the time of diagnosis is a major contributor to the poor prognosis of ovarian cancer (OC) patients. There is a critical need to better understand the mechanism of regulation of metastasis to develop effective treatment strategies targeting the process. Metastasis initiating cells (MICs) have cancer stem cell-like properties along with the ability to invade. Their potential role in OC is unique as the dissemination from the primary tumors involves passive processes like exfoliation. However, the role of […]
- by Baisiwala, S., Fazzari, E., Li, M. X., Martija, A., Azizad, D. J., Sun, L., Herrera, G., Phan, T., Monteleone, A., Nathanson, D. A., Wang, A. C., Kim, W., Everson, R. G., Patel, K. S., Liau, L. M., Prins, R. M., Bhaduri, A.A major obstacle to identifying effective therapies for the aggressive brain tumor glioblastoma is the lack of human-specific, immunocompetent models that reflect the human tumor microenvironment. To address this, we developed the immune-Human Organoid Tumor Transplantation (iHOTT) model. This is an autologous co-culture platform that integrates patient-derived tumor cells and matched peripheral blood mononuclear cells (PBMCs) within human cortical organoids, enabling the study of the patient-specific immune response to the tumor and tumor-immune interactions. This platform preserves tumor and immune […]
- by Bellmunt, J., Xie, Y., Juanpere, N., Munoz, M., Kukreja, S., Liria, S., Li, R., Qiu, X., Jiang, Y., Font-Tello, A., Nunez, M., Epstein, I., Hernandez, S., Lorenzo, M., Menendez, S., Choueiri, T. K., Brown, M. C., LONG, H. W., Cejas, P.High-Grade T1 (HGT1) Non-Muscle Invasive Bladder Cancer (NMIBC) is a clinically heterogeneous disease, characterized by unpredictable treatment responses and limited tools for recurrence prediction. Although molecular classification efforts have been made, patient stratification still primarily relies on clinicopathological features, which offer limited clinical precision. In this study, we integrated chromatin profiling in bulk with single-nuclei(sn) RNA-seq, immunohistochemistry and spatial transcriptomics to define epigenetic subtypes of HGT1, characterize their heterogeneity, and investigate tumor-microenvironment interactions. Our findings reveal distinct chromatin profiles differentiating […]
- by Huang, D., Kwan, T.-K., Ma, S.-L., Tang, N. L.-s.BackgroundNon-translated transcripts (nt-RNAs) with frame-shifts or premature termination codons resulting from alternative splicing events (ASE), have been recently found at unexpectedly abundant in transcriptomes of cancer tissue. However, their full genomic spectrum has not yet been fully elucidated. This study comprehensively characterised the expression of signature junctions of these nt-RNA (termed "toxic junctions" here) of both known and novel nt-RNA across multiple cancer types and investigated their potential as biomarkers. MethodsRNA-seq data of [~]6,000 samples, including the tumor and normal […]
- by Hennigan, R. F., McLaughlin, K., Ratner, N.Loss of NF2 tumor suppressor activity causes NF2-related schwannomatosis. Proximity biotinylation identified proteins proximal to Merlin isoform 1 and isoform 2 at confluence, when Merlin is active, but not in sub-confluent, growing cells. These data confirmed Merlin involvement in cell-cell and cell-substrate junctions, identified new signal transduction pathways, and highlighted a role for Merlin in intracellular transport. Direct binding assays identified the small GTPases RalA and RalB as high affinity PIP2-dependent Merlin binding proteins that co-localized with RalA/B on the […]
- by Freitag, A., Khilji, S. K., Nedielkov, R., Kumar, S. M., Krummhaar, M., Arndt, J., Moreira, G. S. G., Luehle, J., Goerdeler, F., Kamphues, C., Roth, C., Mroginski, M.-A., Seeberger, P., Moeller, H. M., Moscovitz, O.BackgroundSialyl Lewis A (sLeA), or the CA 19-9 marker, is a tetrasaccharide and a tumour-associated carbohydrate antigen (TACA) overexpressed and abnormally secreted as a serum-borne marker in gastrointestinal malignancies. CA 19-9 is the best validated and only FDA-approved serologic marker clinically used to monitor recurrence, progression, and therapy efficiency in pancreatic ductal adenocarcinoma (PDAC) patients. Due to its altered expression on cancer cells, sLeA is also an attractive target for antibody development. Although recent clinical trials have demonstrated insufficient efficacy […]
- by Llombart, V., O'Connor, D., Demeulemeester, J., Bhamra, A., Surinova, S., Turna, A., Fung, K., Wang, L., Li, Y., Rapoz-D'Silva, T., Ahmed, F., Niskanen, H., Stöppelkamp, I., Hnisz, D., Bottaro, S., Fisicaro, C., He, S., Look, A. T., Mansour, M. R.MYC is one of the most enticing therapeutic targets for cancer but clinical-grade inhibitors are still lacking. By site-saturation mutagenesis screening, we identified several evolutionarily conserved acidic patches within the intrinsically-disordered MYC N-terminus that were confirmed to be functionally essential in different cell models and in vivo. Beyond modulating MYCs global transcriptional activity, these negatively charged patches regulate the interaction with chromatin-modifying complexes including those with histone acetyl-transferase activity. One of the key interactions is established with the co-factor TRRAP, […]
- by Daquinag, A. C., AghaAmiri, S., Farmer, S. M., Zhang, S., Ghosh, S. C., Vargas, S. H., Ramesh, A. K., An, Z., Azhdarinia, A., Kolonin, M. G.We have previously reported a cyclic peptide CRAGVGRGC (termed BLMP6) that homes to disseminating tumor cells in mouse cancer models and could be used for metastasis detection and intervention. Here, based on BLMP6 similarity to latent transforming growth factor beta binding protein 4 (LTBP4), we discovered fibulin-4 as a BLMP6 target. We show that BLMP6 mimics the LTBP4 domain binding to fibulin-4 and selectively binds to fibulin-4 in vitro. Fibulin-4 knockout in mouse 4T1 cancer cells abrogated BLMP6 homing to […]
- by Das, B. C., Choudhary, A., Poojary, S., Jain, P., Chaturvedi, H.Triple-negative breast cancer (TNBC) is a clinically aggressive subtype with poor prognosis and limited treatment options. Exosomal microRNAs (miRNAs), encapsulated within secretory vesicles, have emerged as promising biomarkers for cancer detection and monitoring. In this study, we identify five novel exosomal miRNAs–hsa-miR-6803, hsa-miR-1180, hsa-miR-4728, hsa-miR-1915, and hsa-miR-940–that are consistently overexpressed in TNBC cells, stem-like subpopulations, and patient tumor tissues. Integrated analysis of public datasets and in vitro validation revealed that elevated expression of these miRNAs correlates with poor overall survival. […]
- by Chakraborty, A. K., Choudhury, C., Raut, R. D., Bais, M. V.Immunotherapy has transformed cancer therapeutics; however, its impact on oral squamous cell carcinoma (OSCC) remains limited due to acquired resistance, including to Pembrolizumab. To better understand this challenge, we develop a humanized mouse model using immune-deficient NCG mice engrafted with human peripheral blood mononuclear cells (hPBMC), followed by orthotopic implantation of head and neck squamous cell carcinoma (HNSCC) stem cells. This model closely mimics the human tumor-immune microenvironment, showing aggressive tumor growth and metastasis. Pembrolizumab treatment significantly decreases CD8+ T […]
- by Pirttikoski, A., Gall-Mas, L., Senkowski, W., Fontaneda-Arenas, D., Marin Falco, M., Erkan, E. P., Hynninen, J., Wennerberg, K., Vaharautio, A.Core homeostatic programs of tissues, reflected in gene expression modules, can persist through oncogenesis. To reveal how cell states of normal fallopian tube epithelia (FTE) transform into intra-tumoral heterogeneity in ovarian high-grade serous carcinoma (HGSC), we applied a continuous, multi-state approach on single-cell transcriptomes of treatment-naive tumors (n=50) and normal FTE (n=14). We found the gene modules conserved from normal FTE to cancer to be more diverse than those altered during tumorigenesis, wherein the pseudotime-late TNF/NF-{kappa}B-associated module was linked to […]
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