- by Clement, M., Gibbs, A., Begum, A., Siebzehnrubl, D., Kaushik, S., Singh, N., Gupta, B., Eftychidis, V., Siebzehnrubl, F. A.Glioblastomas are incurable and lethal brain cancers. Immunotherapies offer new and promising treatment options for glioblastoma patients, but the highly immunosuppressive nature of these cancers presents a challenging clinical obstacle. Glioblastoma immune evasion is driven by cell-cell interactions in the tumor microenvironment and recent studies have identified astrocytes as important contributors to immune silencing [1, 2]. Cell plasticity is a key feature of reactive astrocytes that drives heterogeneous, pro- or anti-inflammatory states [3], but the molecular regulators of astrocyte-immune interactions […]
- by Patino-Escobar, B., Steinbrunn, T., Perez-Lugo, L., Rampersaud, S., Waller, D. D., Geng, H., Salangsang, F., Paul Phojanakong, P., Camara Serrano, J. A., Steri, V., Aguilar, O. A., Mitsiades, C. S., Wiita, A.Multiple myeloma (MM) orchestrates immune evasion by subverting natural killer (NK) cell function. CD48, one of the most abundant NK-ligands on MM cells, paradoxically enhances NK-cell activation yet is associated with high-risk cytogenetics and poor patient survival. We integrated multi-omics (bulk and single-cell RNA-seq, ATAC-seq), genome-wide CRISPR-KO/a screens, and machine learning to dissect CD48 regulation and function. In human MM and Vk*MYC mice scRNA-seq datasets, NK cells exhibit stepwise increases in inflammatory and exhaustion signatures and loss of cytotoxic potential […]
- by Yamamoto, Y., Takeuchi, K., Tabe, S., Okumura, A., Aoshima, K., Eto, R., Konishi, T., Yamamoto, N., Miyagi, Y., Ohtsuka, M., Tanimizu, N., Taniguchi, H.The specific contribution of tissue-resident macrophages (TRMs) to pancreatic ductal adenocarcinoma (PDAC) progression remains unclear. Here, we found that a high abundance of TRM-derived tumor-associated macrophages (TRM-TAMs) is an independent indicator of poor prognosis in patients with PDAC. To elucidate the underlying mechanism, we established an advanced organoid platform (iMac-FPCO), which incorporates macrophages derived from human induced pluripotent stem cells to reflect the differentiation process of TRMs. Single-cell transcriptomic analysis revealed this model recapitulates the transcriptional identity of TRM-TAMs in […]
- by van IJzendoorn, D. G. P., Przybyl, J., Hastie, T., Bovee, J. V. M. G., Matusiak, M., van de Rijn, M.Introduction Cellular differentiation and lineage commitment are known to be associated with differences in DNA methylation. Leiomyosarcoma (LMS) is a tumor thought to originate from smooth muscle cells in the walls of vessels in the soft tissue (STLMS) or from the uterine myometrium (ULMS). Here, we identify the methylation signatures of normal smooth muscle cells from blood vessels and the uterine wall and compare these with those found in STLMS and ULMS. We hypothesized that these methylation signatures could be […]
- by Bonder, C. S., Ortiz, M., Ffrench, C. B., Webb, S., Toubia, J., Nataren, N. J., Dorward, E. L., Myo Min, K. K., Lonic, A., Arts, P., Cockshell, M. P., Mahoney, M. G., Ebert, L. M., Khew-Goodall, Y.To facilitate survival, migration and evasion of immune surveillance, cancer cells tightly coordinate the synthesis and trafficking of a diverse repertoire of proteins to their cell surface and the surrounding tumor microenvironment. A key mechanism underlying this process is the intracellular membrane trafficking pathways, including vesicular transport systems. There remains a paucity of mechanistic insight into the regulatory components that mediate nascent protein trafficking and their dysregulation in cancer. Herein, we investigate Tumor Protein D54 (TPD54) as a central regulator […]
- by Ramsoomair, C. K., Alvarez, V., Sarmiento, F., Aramburu Berckemeyer, M., Seetharam, D., Kalliecharan, K., Moorkkannur, S. N., Mitchell, J., Hudson, A., Taylor, J., Ceccarelli, M., Bayik, D., Becher, O. J., Prabahakar, R., Welford, S., Gampel, B., De Carvalho, D. D., Reinberg, D., Shah, A. H.Diffuse midline glioma (DMG) is a lethal pediatric brain tumor with no curative therapies. Immune checkpoint blockade (ICB) has shown limited efficacy in DMG, largely due to poor T cell infiltration, low immune checkpoint (IC) expression, and a low tumor mutational burden. Here, we identify adenosine deaminase acting on RNA (ADAR), an RNA-editing enzyme that suppresses endogenous dsRNA sensing, as a key mediator of immune evasion in H3K27M-mutant DMG. ADAR is significantly overexpressed in H3K27M tumors relative to wild-type high-grade […]
- by Woolston, D. W., Churchill, M., Grandori, C., Advani, A., Yeung, C. C. S.Purpose: Glasdegib is a Sonic Hedgehog (SHH) pathway inhibitor used for treating newly diagnosed acute myeloid leukemia in elders or patients unfit for intensive chemotherapy. This study sought to demonstrate growth inhibition and increased apoptosis of B-cell acute lymphoblastic leukemia (B-ALL) in vitro under glasdegib, alone and combined with inotuzumab, using a novel co-culture system and validated chemosensitivity testing model to determine whether glasdegib with and without inotuzumab may represent a promising treatment strategy in B-ALL. Methods: Seven blood and […]
- by Soetje, B., Ma, H., Imtiaz, S., Corbat, A., Grecco, H. E., Schroeder, L., Brueggemann, Y., Seidler, S., Reichl, M., Bastiaens, P. I. H.In early intestinal carcinogenesis, adenoma formation is commonly initiated by loss-of-function mutations in a tumor suppressor that lead to oncoprotein gain-of-function, like in the tumor suppressor-oncoprotein pair APC-{beta}-catenin. Small intestinal organoids provide an in vitro system to study consequences of such mutations on tissue organization. However, conventional genetic manipulations do not allow precise control over the onset and duration of oncoprotein activity to study their influence on tissue transformation. Furthermore, homogenous tissues of clonal genetic models do not readily capture […]
- by Panda, A. K., Sinha, S., Natarajan, K., Jiang, J., Chempati, S., Kazmi, S., Kim, Y.-h., Sharma, S., Schaughency, P., Boyd, L. F., Hernandez, J. M., Margulies, D. H., Shevach, E. M.Background Antibody-mediated blockade of innate receptor-MHC-I interactions represents a promising strategy to enhance anti-tumor immunity, particularly against metastatic cancers resistant to conventional checkpoint inhibitors. In this study, we investigated the effects of the pan anti-MHC-I monoclonal antibody M1/42, which targets MHC-I interactions with Ly49, selectively expressed on murine NK cell subsets. Methods We administered M1/42 to mice and assayed the proliferation and activation immune cells. Anti-tumor activity of growth and metastasis of checkpoint inhibitor-resistant pancreatic ductal adenocarcoma (PDAC) and B16F10 […]
- by Davis, W. J. H., Thompson, M., Farry, S. M., McKinney, C., Gimenez, G., Hatley, M., Kumar, R., Rodger, E. J., Chatterjee, A., Diermeier, S. D., Drummond, C. J., Reid, G.Lung adenocarcinomas frequently harbour actionable oncogenic mutations that are vulnerable to treatment with targeted therapies. While responses to targeted therapies are often initially dramatic, relapse is almost inevitable and prevents durable responses in advanced-stage patients. Relapse is, in part, caused by drug tolerant persister cells (DTPs) which are able to survive treatment by entering a reversible, dormant state. Although long non-coding RNAs (lncRNAs) regulate processes thought to allow DTPs to survive and become stably resistant, the potential roles of lncRNAs […]
- by Fotinos, J., Condat, C. A., Barberis, L.Cancer stem cells (CSCs) exhibit increased resistance to radiotherapy, contributing to tumor recurrence and progression. While CSCs are known for their intrinsic resistance, the role of their spatial organization remains poorly understood. We extend a computational model of tumorsphere growth to investigate how the spatial distribution of CSCs influences radiation response. The model explicitly tracks cell lineages and spatial positions, revealing a preferential accumulation of CSCs in the spheroid interior. Because radiosensitivity increases with oxygen availability, and oxygen levels are […]
- by Papavasileiou, S., Wu, C., Boey, D., Margerie, L., Mo, J., Olsson-Strömberg, U., Söderlund, S., Nilsson, G., Dahlin, J. S.Single-cell RNA-sequencing-based characterization of cells that belong to the neoplastic clone is a major challenge in hematologic neoplasms, where malignant and normal cells coexist. Confident molecular profiling requires simultaneous analysis of gene expression and genetic mutations in individual cells, an ability that is not supported by the standard 10X Genomics workflow. Here, we developed a post-hoc targeted genotyping method for samples processed with the 10X Genomics 3' workflow. To establish the approach, we mixed two types of leukemic cells harboring […]
- by Wolf-Dankovich, G., Mashiah, T., Saad, R., Somech, E., Khoury, H., Tirosh, I., Ben-David, U.Aneuploidy poses a central paradox in cancer biology: it impairs cellular fitness in normal cells but drives cancer progression. To resolve this, we analyzed single cell transcriptomes from >665,000 cells – including ~288,000 malignant cells – across 304 tumors and 15 cancer types. Integrating transcriptomics with inferred aneuploidy profiles, we characterized cell-intrinsic programs and interactions with the tumor microenvironment. Unexpectedly, highly aneuploid single cells exhibited reduced proliferation and metabolism, contrasting sharply with tumor-bulk profiles. We show this divergence is driven […]
- by Diaz Olea, X., Beede, K., Vasconcelos Pereira, G., Scott, D. A., Petucci, C., Martens, E., Rodionov, D. A., Shah, A., Martinez, M. P., Kim, H., Sharma, A. K., Martin, A., Zhang, T., Faries, M. B., Hamid, O., Devkota, S., Osterman, A., Knott, S., Voest, E. E., Ajami, N., Wargo, J., Ramer-Tait, A., Ronai, Z. A.Defining mechanisms used by gut microbiota to control anti-tumor immunity may offer novel therapeutic modalities. Here, we demonstrate that Bacteroides rodentium and closely related Bacteroides uniformis species induce anti-tumor immunity and limit melanoma development when colonized in either germ-free (GF) mice, mice with a complex microbiome, or WT mice. Enhanced CD8+ T cell infiltration seen in tumors of mice harboring B. rodentium coincided with increased expression of immune-stimulating pathways and activation of bone marrow-derived dendritic cells that were co-cultured with […]
- by Duchemin, Q., Trejo Banos, D., Bertolini, A., Ferreira, P. F., Schill, R., Lienhard, M., Wegmann, R., Tumor Profiler Consortium,, Snijder, B., Stekhoven, D., Beerenwinkel, N., Singer, F., Obozinski, G., Kuipers, J.Tumour heterogeneity presents a major challenge for precision oncology, as genetically and phenotypically distinct tumour clones may respond differently to therapy. To address this, we introduce scClone2DR, a probabilistic multi-modal framework that predicts drug responses at the level of individual tumour clones by integrating single-cell DNA and RNA sequencing with ex-vivo drug-screening data. In simulations, scClone2DR substantially outperforms alternatives in recovering true drug effects and clonal sensitivities. Applied to 60 melanoma and 21 acute myeloid leukaemia patient samples, the method […]
- by CHESNEL, F., CHERON, A., AUDIC, Y., ALUSSE, A., DUOT, M., COM, E., LAVIGNE, R., PAILLARD, L., LE GOFF, X.Head and neck squamous cell carcinoma (HNSCC) ranks as the seventh most common cancer, with increasing incidence and mortality rates and limited therapeutic progress. The heterohexameric prefoldin complex, a highly conserved co-chaperone assembly composed of six PFDN subunits, exhibits expression levels strongly correlated with cancer progression. Among these subunits, the PFDN5 gene presents a paradoxical role in cancer biology, demonstrating both tumor-promoting and tumor-suppressive activities. Notably, the PFDN5 gene generates two distinct protein isoforms through alternative splicing, yet their individual […]
- by Kumar, V., Singh, V., Singh, R., Kumar, P., Ghosh, T.Faithful proliferation requires coordinated DNA replication with centrosome maturation and spindle-pole integrity. SLD5, encoded by GINS4, is a core component of the GINS replication complex and is frequently elevated in tumors, but whether it links replication-associated cancer states to centrosome control has remained unclear. Here, we show that GINS4/SLD5 is recurrently upregulated across human cancers at transcript and protein levels and marks tumor programs enriched for DNA replication, chromosome segregation, and mitotic control. In cancer cells, Sld5 depletion dispersed PCM1, […]
- by Senbabaoglu Aksu, F., Cevatemre, B., Degirmenci, N., Kala, E. Y., Ucku, D., Philpott, M., Cribbs, A. P., Dunford, J. P., Oppermann, U., Acilan, C., Bagci-Onder, T.Glioblastoma (GBM) is an aggressive primary brain tumor associated with a median survival of approximately 15 months following diagnosis. Current standard-of-care treatment includes surgical resection followed by radiotherapy and chemotherapy with the DNA-alkylating agent temozolomide (TMZ). However, tumor recurrence in a therapy-resistant state remains a major driver of poor patient outcomes. To investigate the molecular mechanisms underlying TMZ resistance, we generated in vitro models of acquired resistance by exposing initially TMZ-sensitive GBM cells to escalating doses of TMZ. Transcriptomic and […]
- by Bar-Hai, N., Ben-Yishay, R., Arbili-Yarhi, S., Bernstein-Molho, R., Goldinger, G., Balint-Lahat, N., Menes, T., Herman, N., Noy, V., Mansour, A., Globus, O., Hilman, P., Zehavi, Y., Eizenberg-Magar, I., Mahammadov, E., Conrad, T., Rajewsky, N., Antebi, Y. E., Berger, R., Ishay Ronen, D.Epithelial-to-mesenchymal transition (EMT) is activated to equip cells with the capacity to adapt to and escape hostile conditions. While EMT is required for cancer progression, its role in breast cancer initiation remains elusive. Given the basal-like phenotype of breast cancers arising in female carriers of germline BRCA1 pathogenic variants (BRCA1 carriers), we hypothesized that enhanced EMT susceptibility underlies precancerous initiation in mammary epithelium. Perturbation of patient-derived normal mammary organoids from BRCA1 carriers and non-carriers with inflammatory cytokines induced copy number […]
- by Garven, A., Pare, J.-F., Robins, A., Vera-Rodriguez, A., Sampy, R., Bennett, A., Nauman, R. W., Craig, A. W., Greer, P. A., Koti, M., Cotechini, T., Berman, D. M., Simpson, A., Postovit, L.-M., Siemens, D. R., Graham, C. H.The standard-of-care for patients with higher-risk non-muscle invasive bladder cancer (NMIBC) after tumour resection is intravesical administration of Bacillus Calmette-Guerin (BCG). While this form of adjuvant immunotherapy has improved recurrence-free and progression-free survival, a large proportion of patients experience recurrences within a year of diagnosis. The reasons for this high rate of early recurrence following BCG therapy remain unclear; however, inadequate activation of systemic immunity may be a contributing factor. To address this, we analysed the transcriptomic and chromatin accessibility […]
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