- by Iftehimul, M., Newman, R. H., Harrison, S. H., Jones, R. B., Muganda, P. M., Holloman, B. L., Hossain, M. T., Rorie, C. J., Thomas, M. D., Graves, J. L., Kaufman, H. L., Saha, D.Background: The triple-negative breast cancer (TNBC) microenvironment (TME) undergoes progressive reprogramming, transitioning from an early immune-active state to a late immune-suppressed state. While tumor cell plasticity has been extensively studied, the molecular plasticity of T cells in vivo remains poorly defined. Objectives: To characterize transcriptional changes in T cells during TNBC progression and identify stage-specific shifts in T cell function, polarization, and antigen-presenting cell (APC)-T cell interactions. Results: Transcriptional analysis of T cells from BALB/c mice bearing 4T1 tumors at […]
- by Yoo, J. Y., Akter, S., Zuo, Q., Kazemi, A., Wu, W., Goel, M., Lam, A., Dutta, D., Barnick, B., Pekmezci, M., Grosse Perdekamp, M., Soliman, A., Madak-Erdogan, Z.The tumor microenvironment (TME) comprises different cell populations that interact, contributing to tumor heterogeneity and therapy response. Spatial transcriptomics offers valuable insights into transcriptional complexity and heterogeneity of the TME. We established Geographic Information System (GIS)-augmented In-Silico Reconstruction of Tumor Architecture (GIS-ROTA), a biologically informed analytic framework that integrates pathway or cell type-based enrichment analysis with local Morans I to uncover functional spatial domains. In our Visium dataset of primary and metastatic estrogen receptor-positive breast tumor samples, GIS-ROTA revealed extensive […]
- by Giri, S., Selvadurai, B.-R., Simoni-Nieves, A., Gupta, N., Lindzen, M., Chatterjee, R., Genna, A., Van-Daele, M., Ramesh-Kumar, D., Zerbib, M., Oren, R., Meijer, I. S., Wippich, E. F., Avraham, Y., Dahan, R., Kilpatrick, L. E., Platt, S., Hill, S. J., Pal, L. R., Ruppin, E., Romaniello, D., Lauriola, M., Yarden, Y.Resistance of lung cancer to EGFR specific tyrosine kinase inhibitors (TKIs), such as osimertinib, often arises from secondary mutations or the activation of bypass signaling pathways. We noted elevated levels of GAS6 and its receptor, MERTK, in patients acquiring resistance to osimertinib, hence hypothesized that the GAS6 MERTK axis can serve as a therapeutic target. GAS6 promoted cell survival and an anti GAS6 antibody we generated delayed tumor relapses in a xenograft model. Likewise, MERTK ablation sensitized lung cancer cells […]
- by Liu, W., Gupta, A., Kerin, M., Gupta, S.The endoplasmic reticulum (ER) responds to stimuli that disrupt its homeostasis by activating a signalling network known as unfolded protein response (UPR), that restores cellular balance and determines cell fate through three key sensors: IRE1, PERK, and ATF6. Emerging evidence suggests that the UPR regulates the expression of numerous long non-coding RNAs (lncRNAs), which play critical roles in modulating stress responses. Here we show that expression of lncRNA H19 is downregulated in response to ER stress in breast cancer cells. […]
- by Mueller, J., Sofyali, E., Schwarzmueller, L., Aylon, Y., Weizman, E., Schlicker, L., Kelly, K., Borgoni, S., Oz, S., Stocker, C., Burmester, S., Woerner, A., Karolus, S., Michels, B. E., Heiss, D., Will, R., Rodrigues de Melo Costa, V., Lutsik, P., Weichenhan, D., Hofmann, I., Belugali Nataraj, N., Yarden, Y., Magnani, L., Plass, C., Schulze, A., Koerner, C., Oren, M., Wiemann, S.Estrogen receptor alpha (ER)-positive luminal breast cancer is commonly treated with aromatase inhibitors (AI) to block estrogen signaling; however, resistance frequently develops, limiting therapy success. We observed that GLYATL1 (Glycine-N-Acyltransferase Like 1) expression is upregulated in AI-resistant breast cancer cell models and in patients undergoing AI therapy, correlating with poorer survival. Here we demonstrate that GLYATL1 promotes resistance to estrogen deprivation by elevating succinate levels and altering epigenetic histone marks associated with active transcription. Knockdown or knockout of GLYATL1 reverses […]
- by Kutschat, A. P., Frommelt, F., Santini, B. L., Muller, S., Batty, P., Karbon, G., Superti-Furga, G., Seruggia, D.Multiple genetic association studies linked variants at ARID5B with predisposition to B-cell derived acute lymphoblastic leukemia (B-ALL) in children. Still, the molecular function of ARID5B remains largely uncharacterized. Here, we employ a combination of proteomics, genomics and transcriptomics to describe the molecular mechanisms of ARID5B. We identify that ARID5B interacts with MIER1, C16ORF87, HDAC1 and HDAC2 forming a chromatin repressor complex. By CUT&RUN, we mapped ARID5B binding in active regions of the genome, tethering HDAC1 and HDAC2 to distal regulatory […]
- by Liisberg, C., Olsen, F. E.The Somatic Mutation Theory (SMT) frames cancer as a stochastic process driven by the accumulation of random mutations in somatic cells. Using a Poisson-Erlang waiting-time model, we test whether empirical mutation rates and cell-division frequencies permit such multi-hit carcinogenesis within biologically realistic timescales. Even under optimistic assumptions, expected waiting times exceed progenitor-cell lifespans by several orders of magnitude, rendering sequential multi-hit carcinogenesis statistically and biologically implausible. The analysis exposes SMT's internal inconsistencies and supports a paradigm shift from mutation accumulation […]
- by Gong, S., Zhao, Y., Yang, S., Liu, T., Li, C., Zhou, Y., Liang, G.Background: The tumor microenvironment (TME) significantly impacts cancer progression and overall patient survival. However, the complexity of tumor cell-TME interactions in gastric cancer (GC) and their underlying molecular basis remain to be systematically elucidated. Methods: We performed single-cell RNA sequencing (scRNA-seq) on paired tumor and adjacent tissues from 3 treatment-naive GC patients. We conducted an in-depth characterization of the cellular composition and molecular features of the GC TME, with a particular focus on tumor-associated macrophages (TAMs) subsets and their mediated […]
- by Kong, Z., Wang, Y., Zhao, Y., Wang, L., Fan, Z., Shu, Y., Wang, J.Despite the clinical success of cancer immunotherapies, their efficacy is often compromised by antigen-related problems, including heterogeneity, downregulation, loss, and off-tumor toxicity. To overcome these limitations that challenge the current immunotherapies dependent on native antigens, we here describe a new cancer immunotherapy strategy, which artificially and specifically expresses a clinical validated antigen on variant tumors and thus repurposes clinical antibody drugs to treat cancers not belonging to their indications. To authenticate the strategy, we delivered a CD20 gene under a […]
- by Pan, Y., Wang, C., Meng, X., Zhou, W., Hammer, R., Zheng, H., Hildebrandt, G., Kang, X.Acute myeloid leukemia (AML) often enters remission after chemotherapy but frequently relapses due to chemotherapy-resistant leukemic stem cells (LSCs). Relapsed AML remains largely unresponsive to current therapies and carries a poor prognosis. We developed a large-language model (LLM) agent that incorporates multi-modal data to nominate druggable therapeutic targets for AML. We identified that higher expression of AGTR2 (encoding AT2R) is associated with better chemotherapy response and longer survival. In functional studies of 68 primary human AML samples, we found that […]
- by Farndale, L., Rakovic, K., Hatthakarnkul, P., Szalma, S., Schubert Santana, L. P., Martinelli, S., Ballantyne, F., Baird, R. L., Powley, I. R., Officer-Jones, L., Maka, N., Roxburgh, C., Miller, C. J., Chang, D., Edwards, J., Roberts, E. W., Le Quesne, J., Yuan, K.Modern spatial proteomic methods, such as multiplex immunofluorescence (mIF) imaging, offer a data-rich view of spatial biology in intact tissues. However, interpreting its complexity is a major bottleneck, limiting its potential for biological discovery and clinical translation. Current computational methods often rely on segmentation-based approaches that discard crucial morphological information and are limited to testing pre-defined hypotheses. Here, we introduce a self-supervised learning (SSL) framework that enables hypothesis-agnostic, context-aware discovery of biomarkers directly from mIF images. Our approach extracts rich […]
- by Ruan, Z., Li, L., Xiang, W., Zhang, J., Liu, Y., Huang, Z., Wang, Y., Han, X., Yan, C., Ou, Y., Pan, Y., Wei, J., Liu, J., Liu, H.Young women with breast cancer (YBC, age[≤]40) are particularly prevalent in Asian. YBCs usually show more aggressive pathology and poorer outcomes than non-young patients. However, YBCs are underrepresented in current BC risk models, with their tumor intrinsic subtypes and microenvironments lacking a systematic elucidation at the single-cell level, thereby limiting the young-specific therapies. We established a single-cell Chinese YBC landscape baseline, including 246,659 cells, by applying scRNA-seq and scATAC-seq on untreated patients. We developed a cross-modal feature selection algorithm to […]
- by Lim, Y. X., Liu, M., Garb, B. F., Furgal, A., Li, S., Choi, J., Liu, Q., Kopera, H., Hilgarth, R., de Medeiros, M. C., Gonzalez- Maldonado, L., Lanigan, T., McHugh, J., Wolf, G., Mierzwa, M., Baladandayuthapani, V., Rozek, L., Sartor, M., D'Silva, N.Human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC) is now the leading HPV+ cancer in the United States and United Kingdom. Despite high cure rates, a significant subset of patients have aggressive HPV+ OPSCC that recurs; deciphering the underlying mechanisms will identify biomarkers that delineate patient subgroups for personalized treatment. In a comprehensive investigation using complementary clinically-relevant models of HPV+ OPSCC, we demonstrated that elevated expression of a HPV16 E6 spliced isoform (E6*I) compared to full-length E6 (E6FL), is critical […]
- CIViC MCP: Integrating Large Language Models with the Clinical Interpretations of Variants in Cancerby Schimmelpfennig, L. E., Cody, Q., McMichael, J., Coffman, A., Saliba, J., Danos, A., Kiwala, S., Wagner, A. H., Sanz-Cruzado, J., Lever, J., Griffith, M., Griffith, O. L.Summary: The Clinical Interpretation of Variants in Cancer (CIViC) knowledgebase provides a community-driven, open-source platform for discussing the biological and Clinical Significance of molecular variants in cancer. To enable users to make complex connections between CIViC information, we developed the CIViC Model Context Protocol (MCP) server, which allows large language models (LLMs) to directly interface with the CIViC API through natural language, facilitating the rapid summarization of expertly curated cancer variant interpretations. Availability and implementation: The CIViC MCP server is […]
- by Chang, J., Alenizi, S., Zaccaron Milioli, H., Lay, W., Pounraj, S., Li, Y., Shiferaw, M. S., Hosseini Beheshti, E., Kovacevic, Z.Pancreatic cancer (PaC) remains one of the deadliest cancers, with 5-year survival rates of 13%. A major driver of its aggressiveness is the tumour microenvironment (TME), which fuels tumour growth, metastasis, and therapeutic resistance through dynamic, bi-directional communication between cancer cells, fibroblasts, and immune cells. Emerging evidence highlights extracellular vesicles (EVs) as key mediators of oncogenic cross-talk within the PaC TME. This study demonstrates for the first time that the metastasis suppressor NDRG1 significantly influences the biogenesis, cargo packaging and […]
- by Duxfield, A., Garnham, R., Hutton, E., Dowle, A., Wills, J., Luzzi, S., Nelson, R., Lishman-Walker, E., Magee, R., Buskin, A., Hepburn, A. C., Tekoglu, E., Maloney-Friar, K., Frame, F., Maitland, N., Hedley, A., Henderson, H., McCullough, B., Gowardhan, B., Sahadevan, K., McCracken, S., Gaughan, L., Heer, R., Robson, C. N., Coffey, K., Lack, N. A., Signoret, N., Fascione, M., Scott, E.Glyco-immune checkpoints have recently been shown to be critical mediators of immunotherapy resistance across multiple cancer types. In clinical trials, immunotherapeutic treatments for prostate cancer have failed to elicit durable clinical responses. PCa progression is driven by transcriptional networks regulated by key transcription factors including the androgen receptor (AR) and the oncogene MYC. How this crossover between hormone and oncogene-driven signalling pathways regulates tumour glyco-immune checkpoints remains unclear. Here, we show that O-glycans are the major substrates for sialylation in […]
- by PINAULT, M., HERAUD, C., DE OLIVEIRA, M. C., NEAUD, V., VALESCO, V., PROUZET-MAULEON, V., TURCQ, B., Dupuy, J.-W., Raymond, A.-A., Croce, S., SALTEL, F., LAGREE, V., Moreau, V.Endometrial cancer is one of the main gynecological malignancies worldwide, with an estimated 320, 000 new cases annually. Several studies highlight ARHGAP35 as a significantly mutated gene in these tumors. It encodes for the protein p190RhoGAP-A (p190A), which is a major regulator of the small GTPase family of proteins. ARHGAP5 is a paralog of ARHGAP35 that encodes the protein p190RhoGAP-B (p190B). By analyzing human endometrial cancer samples, we found a co-occurrence of mutations in ARHGAP35 and ARHGAP5 genes and we […]
- by Deng, M., Zhou, Z., Lietz, C.Background: Adenocarcinomas are malignancies arising from glandular epithelial cells or secretory tissue, and account for most cancer-related mortalities worldwide, despite advances in treatment. New treatments are often developed in the context of the organ from which the tumor originates. However, there exists shared biology across glandular epithelium at the molecular level regardless of organ system, and there has been a shift towards the molecular classification of tumors. Defining and targeting pan-adenocarcinoma specific molecular features may facilitate the development of treatments […]
- by Chadburn, A., Aguilar Hernandez, M. M., Dai, J., Harrison, M., Reinoso-Vizcaino, N. M., Barry, A. P., Hocke, E., Abramson, K., Chan, C., Cesarman, E., Luftig, M. A., SoRelle, E. D.Non-Hodgkin Lymphoma (NHL) is the main cancer-related mortality for people living with HIV (PLWH). NHL genetic and molecular classifications have been intensely studied and correlated with clinical outcomes, but critical unanswered questions relevant to malignancy persist. For example, tumors positive for Epstein-Barr virus (EBV) are aggressive and account for 30-50% of HIV-associated NHLs, yet insights on the nature of EBV in NHL pathogenesis or potential therapeutic vulnerabilities have been limited. Here, we examined HIV-associated NHLs stratified by histopathologic classification, cell […]
- by BASBOUS, S., SENA, S., DANTZER, C., NEAUD, V., PIQUET, L., GRISE, F., MARTINS, F., Varon, C., GERBAL-CHALOIN, S., FAVEREAUX, A., Colnot, S., LAGREE, V., BILLOTTET, C., Moreau, V.Tumor development and progression are mainly driven by oncogenic mutations but are also regulated by physical factors, such as applied forces or microenvironment stiffness. Through its structural and transcriptional functions, beta-catenin is a key factor that acts on both aspects to promote liver tumorigenesis, leading to hepatocellular carcinoma (HCC) development. However, the mechanisms by which these two functions regulate downstream targets remain poorly understood. Herein, we describe Rnd3, also called RhoE, an atypical member of the Rho GTPase family, as […]
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