- by Yeung, S. F., Chan, M. S. M., Law, C. T. Y., Law, A. C. H., Lee, C., Leung, A. M. F., Chau, M. P. K., Chan, H. H. Y., Chen, J. X., Ko, B. C. B., Chan, K. K. L., Cho, W. C., Tsui, S. K. W.Melanoma in Asia presents a unique epidemiological profile, with a higher prevalence of acral and mucosal subtypes compared to Western populations. WhileKITmutations are found in up to 15% of Asian melanoma cases, clinical outcomes with KIT inhibitors have been modest due to heterogeneous mutation profiles and a lack of specific patient selection criteria. This study characterizes the landscape of KITmutations in melanoma using the GENIE database, identifying 86 recurrent hotspots, many of which are variants of unknown significance (VUS). We […]
- by Smith, M. G., Ramos, A. R., Panchal, H., Cerkezi, N. H., Garcia, C., Spruce, L., Fazelinia, H., Maggi, L. B., Mailloux, A. W.Induction of the MHC class I antigen processing and presentation pathway (C1APP) is a critical part of the IFN-g; response necessary for effective cytotoxic immunity against tumors of epithelial origin1,2. Loss of this response is associated with worse disease outcomes and renders patients refractory to immunotherapies3-6. Without C1APP induction, tumor cells cannot optimally process and present immunopeptides from tumor-associated antigens (TAA) and neoantigens to effector cytotoxic T cells7-9. Here, we show that physiologic levels of hypoxia block induction of the […]
- by Widodo, S. S., Dinevska, M., Stylli, S. S., Dolcetti, R., Mazzieri, R., Faridi, P., Lim Kam Sian, T. C., Mangiola, S., Ali, L. A., Vettorazzi, S., Tuckermann, J., Hao, M., Stamp, L., Berrocal-Rubio, M. A., Barrow, A. D., Cook, L., Mantamadiotis, T.Tumor-associated macrophages (TAMs) are key mediators of tumor immunosuppression, yet the factors governing their polarization remain poorly understood, especially in highly immunosuppressive cancers, including cancers affecting the central nervous system. This study investigates the molecular pathways underlying TAM polarization in glioblastoma, one of the most immunosuppressive cancer types. Using a multi-omics approach integrating spatial proteomics, RNA-sequencing, and proteomic profiling of tumor cells and macrophages, we demonstrate that circulating monocytes polarize toward an immunosuppressive state when they exit tumor blood vessels, […]
- by Faber, A. C., Floros, K. V., Dozmorov, M., Koblinski, J., Lorenz, M. R., Kraskauskiene, V., Hu, B., Zhang, K., Kehinde, V., Xing, Y., Roberts, J., Slaughter, J. M., Kurupi, R., Dalton, K. M., Hill, R. D.Neuroblastoma (NB) is the most common extracranial solid tumor in children. Relapsed or refractory (R/R) high-risk (HR) NB tumors continue to exhibit poor outcomes despite intensive and protractive multimodal therapy. Activating mutations in the RAS- mitogen-activated protein kinase (MAPK) pathway are frequently observed in R/R HRNB. The early promise of ALK inhibitors to treat ALK-mutant NB underscores the ability of appropriate targeted therapies to improve outcomes for HRNB patients. While MAPK pathway activation is prominent in HRNB, FDA-approved MEK inhibitors […]
- by Rusten, T. E., Teles-Reis, J., Dillard, C., Antunes, M. G., Jain, A., Ruiz-Duran, P., Deng, M., Liu, D., Gaudin, C., Nakken, S., Singh, A., Baumgartner, M. E., Dahlstrom, A. M., Reinertsen, V.Cancer is generally thought to be caused by expansion of a single mutant cell. However, analyses of human early lesions show that tumours can originate from several genetically distinct cell populations. How neighbouring mutant clones interact to shape tumourigenesis, and which driver genes mediate these effects is largely unexplored. Here, we use an in vivo mosaic Drosophila epithelial model to systematically test interclonal interactions during early Ras-driven tumourigenesis. We screened 88 recurrent RAS co-mutated driver genes in human carcinomas for […]
- by Schaaf, C. R., Hutchins, D. R., Liu, T., Kooshki, M., Wagner, C., Edenhoffer, N., Wajih, N., Forsythe, S., Greissinger, R., Levine, E., Shen, P., Triozzi, P., Miller, L. D., Hall, A. R., Soker, S., Votanopoulos, K. I.Harnessing patient immune cells via adoptive cellular therapy is a promising cancer therapeutic strategy. However, major challenges remain for advanced solid malignancies, including difficulty isolating sufficient tumor infiltrating lymphocytes (TILs) and limited targeting of diverse neoantigens in heterogenous tumors. To address this, we have developed a tumor-on-a-chip platform with co-cultured patient-derived tumor cells, autologous peripheral blood mononuclear cells (PBMCs), and lymphoid tissue-derived antigen presenting cells. This approach generates organoid interacting lymphocytes (OILs) with enhanced anti-tumor activity. In peritoneal malignancies, OIL-induced […]
- by Karlow, J. A., O'Connor, C., Sharaf, R., Pavlick, D. C., Savol, A., Darcy, C., Kakumanu, A., Camara, W., Walsh, M., Janovitz, T., Kelley, M. J., Serway, C. N., Mitchell, J., Elvin, J. A., Montesion, M., Burns, K. H., Frampton, G. M.MET exon 14 skipping is a pathogenic event that results in decreased ubiquitin-mediated degradation of the MET receptor, sustained oncogenic signaling, and conferred sensitivity to MET tyrosine kinase inhibitors. While exon 14 skipping is most commonly caused by somatically acquired base substitutions and small indels near the exon 14 splice sites, here we report nine cases in which long interspersed element-1 (LINE-1, L1)-mediated insertions within or adjacent to MET exon 14, including one case of a LINE-1-mediated pseudogene insertion, appear […]
- by Orellana, E. A., Bowles, I. E., Yang, X., Torres, A., Jamieson, S. R., Ali, R. H., Gutierrez, A., Gregory, R. I.tRNAs play a critical role in protein synthesis, influencing mRNA translation dynamics to shape proteomes. Emerging evidence links dysregulated tRNA activity to cancer progression, with tRNA-Arg-TCT identified as an oncogenic driver when ectopically overexpressed in non-malignant cells. The requirement of endogenous tRNA-Arg-TCT in cancer biology, however, remains untested. Moreover, considering that the tRNA-Arg-TCT family comprises six genes in humans, the importance of an individual tRNA isodecoder in cancer remains unknown. Here, we find elevated levels of tRNA-Arg-TCT-4-1 isodecoder are associated […]
- by Yeung, S. F., Chen, J. X., Law, C. T. Y., Law, A. C. H., Lee, C., Leung, A. M. F., Chau, M. P. K., Ko, B. C.-B., Wu, Y., Liang, K., Cho, W. C., Siu, M. K. Y., Chan, K. K. L., Tsui, S. K. W.NRAS mutations drive 20 to 30% of melanomas and are associated with poor response to immunotherapies. RAS(ON) inhibitors such as daraxonrasib (RMC-6236) have shown promising activity in NRAS-mutant melanoma, yet mutation-specific sensitivity, resistance mechanisms, and rational combination strategies remain largely unresolved. Here, we performed saturation mutagenesis across NRAS mutation hotspots to systematically evaluate mutation-resolved oncogenic fitness and drug responsiveness to six direct RAS inhibitors (sotorasib, adagrasib, ADT-007, BI-2865, RMC-6236, and RMC-7977) using isogenic melanoma spheroids, xenografts, and pooled drug-sensitivity profiling. […]
- by Lingo, J. J., Reis, R., Allamargot, C., Raygoza Garay, J. A., Kaemmer, C. A., Elias, E. C., Voigt, E., Jabbari, A., Wilhelm, C. R., Boyden, A. W., Karandikar, N. J., Breheny, P., Meyerholz, D. K., Dodd, R. D., Houtman, J. C., Darbro, B. W., Quelle, D. E.In most cancers, intratumoral plasma cells prognose better patient survival and response to immune checkpoint blockades (ICBs), but their importance to ICB therapy response has never been tested. Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that lack effective therapies. Recent work in de novo MPNSTs showed dual inhibition of cyclin-dependent kinases 4/6 (CDK4/6) and MEK increases intratumoral plasma cells and sensitizes tumors to anti-programmed death-ligand 1 (PD-L1) therapy. We generated de novo MPNSTs in wild-type and plasma cell-deficient […]
- by Majeed, M., Akram, M. Z., Tariq, H.Triple-negative breast cancer (TNBC) is an aggressive subtype that lacks effective targeted therapies. This study aimed to identify robust prognostic biomarkers by integrating network biology with machine learning (ML) approaches. TNBC expression cohorts were analysed to identify differentially expressed genes (DEGs) and crucial gene clusters via limma and Weighted Gene Co-expression Network Analysis (WGCNA). In results, 579 DEGs were identified, and network analysis revealed two TNBC-associated modules. Overlapping determined 208 genes enriched in cell-cycle and mitotic-regulation pathways. To identify candidate […]
- by Hong, L., Liu, M., Sridhar, S., Ong, Z. Y. C., Tay, S. C. N., Lai, W. X. C., Tipgomut, C., Jaynes, P., Peng, Y., Tan, C. L., Hue, S. S.-S., Ng, S.-B., Mel, S. D., Poon, L., Batumalai, Y., Jayalakshmi,, Brooks, J., Hamberger, F., Lane, B. J., Jimenez-Sanchez, D., Braubach, O., Pan-Hammarstrom, Q., Sudharshan, R., Tsang, A., Rao, A., Keller, E. T., Hawula, Z., Burgess, M., Tuczko, N., Keane, C., Ponzoni, M., Tripodo, C., Jeyasekharan, A. D.Primary central nervous system lymphoma (PCNSL) is a subtype of diffuse large B-cell lymphoma (DLBCL) with confined CNS growth. We evaluated tumor microenvironment (TME) features associated with its unique tropism. Comparative spatial transcriptomic profiling of PCNSL samples (n=17) revealed increased macrophage infiltration compared to systemic DLBCL (n=76). These macrophages showed enrichment of immunosuppressive (SPP1) and cholesterol metabolism signatures. These findings were validated across three independent PCNSL scRNA-seq cohorts (n=8,7,13), with further characterization as lipid-laden macrophages (LLMs)- like those noted in […]
- by Zereg, E., Voisin, L., Courcelles, M., Brochu, S., Gombos, M., Bonneil, E., Karl, G., Jung, S., Perreault, C., Tirode, F., Thibault, P., Meloche, S.Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas that are largely incurable with no clinically effective systemic therapies or immunotherapies for advanced disease. Here, we identify the SRC-family kinases (SFKs) YES and SRC as redundant, essential drivers of MPNST growth. Dual inhibition of YES/SRC activity by genetic silencing or pharmacological SFK inhibitors markedly suppressed the proliferation of multiple NF1-mutant MPNST cell lines. In vivo, conditional genetic depletion of YES/SRC in MPNST cells abrogated tumor growth in […]
- by Peng, M., Keith, K., Dalwadi, S., Anderson, V. E., Resnick, A., Falk, M. J.Osteosarcoma is the most common pediatric bone tumor yet has limited treatment options, especially for metastatic cases with a 20% adjusted 5-year survival rate. Current therapies are non-specific, involving primary tumor resection with DNA-damaging chemotherapies like methotrexate, doxorubicin, and cisplatin. Few effective treatment options exist for metastases. Targeting metabolism involving cancers reduced mitochondrial functionality remains underexplored in osteosarcoma. We investigated the therapeutic potential in human osteosarcoma primary and metastatic cell lines of metabolic modulating drugs including metformin, cycloheximide, mitochondrial ETC […]
- by Kurlekar, S., Lima, J. D. C. C., Kupfer, N., Pugh, C. W., Mole, D. R., Adam, J., Ratcliffe, P. J.Inactivation of VHL is a truncal alteration in clear cell renal cell carcinoma, but additional events are required for oncogenesis, most commonly PBRM1 inactivation. To better understand this co-operation, we used an oncogenic cell-tagging strategy to analyze the earliest transcriptional and cellular consequences of Vhl and/or Pbrm1 inactivation in the renal tubular epithelium, in vivo, at single-cell resolution. Pbrm1 inactivation did not globally alter HIF-dependent transcription or increase early tubular proliferation induced by Vhl inactivation. Instead, it had independent effects […]
- by Swain, A., Mathur, A., Soni, N. D., Wilson, N., Benyard, B., Jacobs, P., Khokhar, S. K., Kumar, D., Haris, M., Reddy, R.Introduction: Glioblastoma is characterized by heterogeneous tumor characteristics and infiltrative tumor boundaries, making accurate delineation difficult with extensive manual annotations. Chemical exchange saturation transfer (CEST) is a non-invasive MRI technique used for in vivo assessment of metabolic and macromolecular information through a Z-spectrum. CEST may provide insight into metabolic changes present in early-stage disease that are not visible in routine clinical imaging, thereby improving tumor delineation. In this work, we use an unsupervised anomaly detection (UAD) strategy to learn the […]
- by Terrazzan, A., Ancona, P., Carbone, F. P., Trevisan, P., Zuccato, C., Szymanek, E. A., Szelag, M., Brugnoli, F., Zaczek, A., Gaj, P., Swierniak, M., Calabro, L., Agnoletto, C., Palatini, J., Bianchi, N., Duchnowska, R., Senkus, E., Jazdzewski, K., Kaminski, T. S., Volinia, S.Circulating tumour cells (CTCs) represent a minimally invasive method for monitoring cancer evolution in patients. CTCs are nowadays commonly isolated using antibodies against EPCAM protein. A key limitation regards the extent of EPCAM-negative CTCs, such as those that undergo EMT or whose tumour of origin is EPCAM-low or negative. We studied 3,302 RNA single-cell transcriptomes reported as CTCs in public repositories. Using copy number variation and cell type-specific markers, we discriminated bona fide CTCs from contaminating blood cells, often mislabelled […]
- by Paluncic, J., Carrero, Z. I., Fischer, L. K., Schulz, J. P., Hanf, D., Jady, A., GutierrezTenorio, F., Klimova, A., Dagostino, C., Wolf, I., Huether, M., Werner, M., PourabbasTahvildari, P., Hrabovska, S., Santos, M. G., Young, E., Mateska, I., Schulze, S., Prause, R., Peterziel, H., Kirchberg, J., Stange, D. E., Schmidt, B., Huebschmann, D., Scholl, C., Schneider, M., Westphal, D., Wurm, A. A., Oehme, I., Witt, O., Pablik, J., Venkataramani, V., Heilig, C. E., Kreutzfeldt, S., Horak, P., Moehrmann, L., Kerle, I., Richter, S. M., Weitz, J., Schaser, K., Richter, D., Frohling, S., Heining, C.,Rare cancers are individually uncommon but collectively represent a substantial share of cancer burden, with limited systemic treatment options for many entities. Molecular profiling identifies targetable alterations, but actionable findings are limited and responses can vary despite a matched target. This motivates complementary approaches that directly assess tumor drug response. Here, we establish a biopsy-compatible ex vivo drug sensitivity testing platform optimized for low input and reproducibility. Patient-derived material was tested either directly or following ex vivo expansion. Functional profiling […]
- by Vasudevan, K., T, D., Kumar Selvam, P., Krishnan, A., B G, S., Mudipalli Elavarasu, S., Mohan, S., Karunakaran, R.Triple negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype with limited therapeutic options. In this study, we performed an integrative analysis of TNBC genomics data, including gene expression, somatic mutations, copy number alterations, survival outcomes, immune profiling, and clustering, to identify potential neoantigens, patient populations suitable for vaccination, and biomarkers for evaluating vaccine efficacy. This Integrated analysis identified POSTN and CAP1 as tumor specific antigens. Incorporation of TNBC specific mutations into the screened wild-type antigens led to […]
- by Mottaghi-Dastjerdi, N., Soltany-Rezaee-Rad, M.Gastric cancer (GC) is a major cause of cancer mortality and remains difficult to diagnose early and treat effectively. Although transcriptomic profiling has defined extensive molecular heterogeneity, many studies are not anchored to clinicopathological variables or interpreted in the context of tissue-level pathobiology. We applied an integrative transcriptomic and network-based framework to identify molecular signatures that reflect structural and biochemical reprogramming of gastric tissue during malignant transformation. RNA-seq expression profiles and clinical annotations were analyzed using non-parametric differential expression filtering, […]
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