- by Ebinumoliseh, I., Bijukumar, G., Hoff, K., Brayer, K. J., Bearer, E. L., Ness, S., Edwards, J. S.Adenoid cystic carcinoma of the salivary gland (SGACC) is a highly aggressive malignancy characterized by poor patient survival outcomes. While several studies have analyzed the transcriptome of the salivary gland at the bulk and single-cell level, no spatial transcriptomic analyses of this tissue have been published. Most of the existing publications on SGACC have predominantly relied on bulk and single cell RNA sequencing approaches, which do not resolve the spatially localized transcriptional heterogeneity nor have the resolution for defining molecular […]
- by HUBER, M., GHOSSOUB, R., Leblanc, R., David, G., Zimmermann, P., THUAULT, S.Extracellular matrix (ECM) remodelling is essential for tumour progression. The metalloproteinase MT1-MMP promotes cell invasion by degrading ECM components. MT1-MMP accumulates at invadopodia, actin-rich structures mediating ECM degradation, and is also present on the surface of small extracellular vesicles (sEV), key players in cell-to-cell communication. The role of sEV-associated MT1-MMP in ECM degradation and the mechanisms supporting MT1-MMP loading into sEV are unknown. We previously established that the syntenin PDZ protein, in association with the syndecan (SDC), is essential for […]
- by Inchiosa, M. A.This study follows from the novel findings in our previous publication that {beta}2-adrenergic receptor ({beta}2AR) agonists show gene-expression signatures that are consistent with glucocorticoid receptor (GR) agonists. These observations were made with analytical software associated with the Harvard/MIT genomic database, CLUE. This formed a hypothesis that {beta}2AR agonists would share the anti-inflammatory activity of GR agonists and their ability to induce apoptosis in tumors of lymphatic lineage. Our lead {beta}2AR agonist from our previous study, levalbuterol, was tested for inhibitory […]
- by Counts, B. R., Jean, S., Gaafer, O., Ota, S. K., Inabathini, I., Guo, T., Guttridge, D. C., Ostrowski, M. C., Koniaris, L. G., Cao, S., Roh, H. C., Zimmers, T. A.Skeletal muscle loss in pancreatic cancer is a significant cause of morbidity and mortality for patients. In order to understand myocytes changes we examined myonuclei- and myofiber-specific dynamics during pancreatic cancer cachexia progression. Single-nucleus RNA-seq was used to interrogate myonuclear gene expression, and RNAscope and immunofluorescence characterized myofiber-specific changes. Bulk RNA-seq of skeletal muscle provided a whole-muscle transcriptomic profile. Cachexia induces a progressive loss of muscle differentiation factor Maf and its target Myh4, accompanied by increased expression of Myh1 and […]
- by Ben Shalom, I., Somer, J., Miyara, S., Mayo, A., Mannor, S., Alon, U.Cell populations in human tissues change over time by cell division, death and transitions between functional states. In the tumor microenvironment (TME), such dynamics are central to immune evasion, stromal remodeling and therapeutic response. However, it is difficult to measure such dynamics in vivo because usually only a single biopsy is available providing a static snapshot. To obtain cell population dynamics from a snapshot we previously developed One Shot Dynamic Reconstruction (OSDR1.0), an algorithm that reconstructs cell population dynamics over […]
- by Hosny, N., Li, S., Amend, S. R., Gatenby, R., Pienta, K., Brown, J., Qu, J., Austin, R. H.Most cancer deaths result from metastasis, yet only a rare subset of tumor cells can complete this process. Among these, polyaneuploid cancer cells (PACCs), which arise via endoreplication under stressors such as hypoxia, are implicated as metastatic drivers, but how they acquire this potential is poorly understood. Here, we show that prostate cancer-derived PACCs exhibit features predictive of invasion and intravasation. Time-lapse fluorescence microscopy and single-cell tracking under hypoxia revealed that PACCs migrated significantly farther than Non-PACCs, consistent with local […]
- by Meng, W., Das, A., Sinha, H., Naous, R., Bracci, P., McGrath, M., Huang, Y., Gao, S.-J.Kaposi's sarcoma (KS) is a highly inflammatory, angiogenic tumor driven by Kaposi's sarcoma-associated herpesvirus (KSHV), yet the origins of tumor cells and mechanisms of progression remain unclear. Here, we present the first spatial single-cell atlas of KS, profiling 256 samples across patch, plaque, and nodular lesions and normal controls. We identify CD34+ progenitor lymphatic endothelial cells (LECs) as the primary targets of KSHV, whose clonal expansion drives tumor growth. KSHV infection induces widespread cellular reprogramming across the tumor microenvironment, including […]
- by Hwang, S.-Y., Nikolli, H., Yoval-Sanchez, B., Yang, S., Martin, P., Gribbin, C., Sehgal, L., Alinari, L., Baiocchi, R. A., Hwang, I., Huang, X., DiLiberto, M., Galkin, A., Kwak, H., Chen-Kiang, S., Zheng, H., Paik, J.Resistance to Bruton's tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies, limiting treatment durability. Here, we identify ferroptosis suppression as a central mechanism of BTKi resistance in mantle cell lymphoma (MCL). Aberrant BRG1 activity protects cells from BTKi-induced ferroptosis by restricting reactive oxygen species (ROS) and labile iron. Mechanistically, BRG1 promotes resistance through both BTK-dependent survival signaling and a BTK-independent transcriptional program. The latter is mediated by BRG1-driven induction of MEF2B, which upregulates NDUFA4L2 to inhibit […]
- by Fabbri, L., Lagadec, L., Guerin, E., Lecourt, H., Baille, D., Besse, L., Messaoudi, C., Desaubry, L., Abou-Hamdan, H., Roy, S., Lombard, B., Loew, D., Scoazec, J.-Y., Robert, C., Vagner, S.During their inevitable evolution towards acquired resistance to anti-cancer targeted therapies, cancer cells adopt distinct gene expression profiles that allow them to transiently adapt to and tolerate the treatment. Similar to bacterial cells that transiently tolerate antibiotics, cancer cells surviving therapy can increase their mutation rate, enhancing the likelihood of acquiring resistance-conferring mutations and evolving into resistant cells. This adaptive mutability has been linked to transcriptional reprogramming of DNA damage repair mechanisms and effective therapeutic strategies to target such mechanisms […]
- by Mohammadnejad, N., Hillen, T.Oncolytic virotherapy (OVT) represents an innovative and promising therapeutic method for cancer treatment. This approach involves the introduction of oncolytic viruses into the patient, which are engineered to selectively target and lyse tumor cells. Based on previous mathematical modelling of oncolytic viruses, we consider a mathematical model that describes the intricate interactions between the oncolytic virus, cancer cell populations, and the immune system. Our study includes a detailed qualitative and quantitative analysis of the model to explain why, despite their […]
- by Ng, J., You, Y., Zhang, T. Z., Hess, J. B., Best, S. A., Caneborg, A., Schmiel, M., Godfrey, D. I., Wu, Y., Tothill, R. W., Antilla, C. J. A., Baldwin, T. M., Naik, S. H., Amman-Zalcenstein, D., Kersbergen, A. J., Leong, T. L., George, J., Ritchie, M. E., Gherardin, N. A., Koay, H.-F., Hickey, P. F., Steinfort, D., Sutherland, K. D.Small cell lung cancer (SCLC) is a highly aggressive neoplasm with limited sensitivity to anti-PD-(L)1 blockade, likely due to the epigenetic silencing of MHC-I. Elucidating MHC-I-independent immune recognition mechanisms is therefore crucial for enhancing treatment responses and improving clinical outcomes in a greater number of patients. Leveraging single cell approaches, we discovered {gamma}{delta} T cell infiltration in biospecimens from patients with SCLC. Despite PD-1 expression, {gamma}{delta} T cells maintained a cytotoxic transcriptional profile, suggestive of an anti-tumor role. Indeed, high […]
- by Taglang, C., Batsios, G., Gillespie, A. M., Phillips, J. J., Taylor, J. W., Viswanath, P.Mutations in isocitrate dehydrogenase (IDHm) define a distinct molecular class of gliomas. IDHm converts alpha-ketoglutarate (alpha-KG) to the oncometabolite D-2-hydroxyglutarate (D-2HG), which drives tumorigenesis. The IDHm inhibitor vorasidenib suppresses D-2HG production and extends progression-free survival in some, but not all, IDHm glioma patients. Here, using clinically relevant patient-derived IDHm models and patient tissue, we show that phosphoglycerate dehydrogenase (PHGDH) drives intrinsic resistance to vorasidenib by promiscuously converting alpha-KG to D-2HG and maintaining D-2HG concentration despite IDHm inhibition. Silencing PHGDH sensitizes […]
- by Newsom-Stewart, C. M., Bhatt, D. P., Major, M. B., Kaufman, C. K.The transcription factor SOX10 is a central regulator of melanoma biology, influencing tumor initiation, progression, phenotypic plasticity, and therapeutic resistance. However, the molecular mechanisms underlying these diverse functions remain incompletely understood. To elucidate the protein-protein interactions (PPIs) that mediate SOX10 activity in melanoma, we mapped the human SOX10 (hSOX10) interactome for the first time in human melanoma cells (A375 line). Given the challenges of capturing transient and weak transcription factor interactions, we employed miniTurbo (mT) proximity-dependent biotinylation coupled with mass […]
- by Calado, D. P., Boulat, V., Alberts, E., Driscoll, P. C., Hung, M. S., Cunha, A., Quist, J., Liu, F., Brundin, C. A., Bhalla, A., Avalle, L., Rosekilly, J., Ryan, L., Gillett, C., Strom, M., Poli, V., MacRae, J. I., Grigoriadis, A.Tertiary lymphoid structures (TLS) and B cell infiltration are strong predictors of immunotherapy success across cancers, including triple-negative breast cancer (TNBC). However, immune-cold TNBCs often lack both features. Here, we identify a tumor-intrinsic mechanism that actively suppresses B cell recruitment. Despite evidence of B cell responses in cancer-associated lymph nodes (cLNs), B cells fail to infiltrate TNBC tumors or form TLS. This exclusion is not simply due to chemokine deficiency as exogenous chemokine addition fails to restore B cell migration. […]
- by Chutoe, C., Webb, E. R., Muir, M. T., Laing, F., Brunton, V. G., Kriegsheim, A. v.Triple-negative breast cancer (TNBC) is one of the most aggressive and treatment-resistant breast cancers. Although immunotherapy has emerged as a promising treatment option, clinical benefit is limited, with only around half of patients responding, even when combined with standard chemotherapeutic agents. This limited efficacy is often attributed to immunologically ''cold '' tumour microenvironments (TME), which are resistant to current immunotherapies. Addressing this challenge requires approaches that can reprogram ''cold '' TMEs into ''hot '' immune-responsive states. USP18, a negative regulator […]
- by Monavarian, M., Sherman, A. R., Mohammad, I. A., Maddineni, S., Zhang, M., Wu, J. C., Chua, K. F., Sunwoo, J., Finegersh, A.ACTL6a is an essential component of SWI/SNF and expressed on the chromosome 3q26 cytoband, which is amplified in head and neck squamous cell carcinomas (HNSCC). While ACTL6A is emerging as an oncogene, its role as a treatment target and mechanisms of transcription factor induction remain unknown. Here, we show that ACTL6A expression is a mediator of the Warburg effect, with ACTL6A knockdown inducing mitochondrial dependency and significantly decreasing levels of aerobic glycolysis. These effects lead to near complete attenuation of […]
- by Corveleyn, L., Provez, L., Satilmis, O., Refhagen, N., Landfors, M., Sleeckx, W., Lintermans, B., De Maesschalck, A., Kotecha, R. S., De Moerloose, B., Lammens, T., Deforce, D., Degerman, S., Goossens, S., Van Vlierberghe, P., Dhaenens, M.Epigenetic modifications are dynamic and reversible, making them attractive targets for therapeutic intervention in cancer. Although several epigenetic drugs (epidrugs) have been clinically approved, their application in T-cell acute lymphoblastic leukemia (T-ALL) remains limited, and predictive biomarkers of response are lacking. Here, we present a mass spectrometry (MS)-based pharmacoepigenetic approach to profile histone post-translational modifications (hPTMs) to identify signatures associated with epidrug sensitivity in T-ALL. Baseline hPTM landscapes were previously established by our group for 21 T-ALL cell lines using […]
- by Araujo, T. M. T., Rodrigues, B., da Silva, J. M. C., Remigio, M., Moreira, F., Moraes Casseb, S. M., Barra, W. F., Ishak, G., Anaissi, A. K. M., Magalhaes, L., Vidal, A., Mourao, R., Teixeira, E., Pereira, D., Silva, V., Avelar, D., Silva, R., Santos, A., Marques, L., Burbano, R. M., Assumpcao, P. P.Alanyl aminopeptidase (ANPEP) has been implicated in various cancers, but its specific role in gastric adenocarcinoma (GC) remains incompletely understood. This study analyzed ANPEP gene expression in gastric cancer (GC), peritumoral tissue (PTT), metaplasia (M), and normal tissue (N). Total RNA was extracted, libraries were prepared and sequenced on the Illumina NextSeq 500. Data was processed using the nf-core/rnaseq pipeline. Transcript quantifications were imported with tximport and normalized using DESeq2. Differential expression (|log2;FC| >2; adj. p < 0.05) and Kruskal […]
- by Timpanaro, A., Song, E. Z., Toumi, R., Elena-Sanchez, L., Meechan, M., Piccand, C., Nemec, K., Kordowski, A., Lau, D., Johnson, S., Winter, L., Rajendran, A., Ronsley, R., Oda, S. K., Gustafson, J., Wendler, J. P., Koschmann, C., Evans, M., Pattwell, S., Jensen, M. C., Foster, J. B., Dun, M. D., Biery, M. C., Vitanza, N. A.Background. Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor affecting over 300 children annually in the United States. Chimeric antigen receptor (CAR) T cells are a targeted immune effector cell therapy with substantial clinical benefit against hematologic cancers. Against CNS tumors, CAR T cells targeting B7-H3, a protein highly expressed on DIPG, have rapidly advanced from preclinical studies to clinical trials. BrainChild-03 (NCT04185038), a phase 1 trial of repeatedly delivered intracerebroventricular (ICV) B7-H3-targeting CAR T cells (B7-H3 […]
- by Ratnawati, H., Sanjaya, A., Christiandy, A., Young, L. S., Ott, S.BackgroundEpstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is characterized by extensive immune infiltration, yet immune evasion remains a hallmark of the disease. In this study, we aimed to leverage publicly available datasets to identify EBV-host gene interactions and re-map their expression at single-cell resolution. MethodsWe conducted a meta-analysis of transcriptomic datasets to identify differentially expressed genes in NPC, mapped these genes to EBV-host interaction data, and constructed a network. Network clustering and pathway enrichment were performed, and single-cell RNA sequencing datasets […]
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