bioRxiv - Cancer Biology最新文献

{"title":"DNA methylation status classifies pleural mesothelioma cells according to their immune profile: implication for precision epigenetic therapy","authors":"Maria Fortunata Lofiego, Rossella Tufano, Emma Bello, Laura Solmonese, Francesco Marzani, Francesca Piazzini, Fabrizio Celesti, Francesca Pia Caruso, Teresa Maria Rosaria Noviello, Roberta Mortarini, Andrea Anichini, Michele Ceccarelli, Luana Calabro', Michele Maio, Sandra Coral, Anna Maria Di Giacomo, Alessia Covre","doi":"10.1101/2024.08.08.607174","DOIUrl":"https://doi.org/10.1101/2024.08.08.607174","url":null,"abstract":"Background: co-targeting of immune checkpoint inhibitors (ICI) CTLA-4 and PD-1 has recently become the new first-line standard of care therapy of pleural mesothelioma (PM) patients, with a significant improvement of overall survival over conventional chemotherapy. The analysis by tumor histotype demonstrated a greater efficacy of ICI therapy in non-epithelioid (non-E) vs. epithelioid (E) PM; although some E PM patients also benefit from treatment. This evidence suggests that molecular tumor features, beyond histotype, could be relevant to improve the efficacy of ICI therapy in PM. Among these, tumor DNA methylation emerges as a promising factor to explore, due to its potential role in driving the immune phenotype of cancer cells. Thus, we utilized a panel of cultured PM cells of different histotype, to provide preclinical evidence supporting the role of the tumor methylation landscape and of its pharmacologic modulation, to prospectively improve the efficacy of ICI therapy of PM patients.\u0000Methods: the methylome profile (EPIC array) of distinct E (#5) and non-E (#9) PM cell lines was analyzed, followed by integrated analysis with their associated transcriptomic profile (Clariom S array), before and after in vitro treatment with the DNA hypomethylating agent (DHA) guadecitabine. The most variable methylated probes were selected to calculate the methylation score (CIMP index) for each cell line at baseline. Genes that were differentially expressed and methylated were then selected for gene ontology analysis.\u0000Results: the CIMP index stratified PM cell lines in two distinct classes, CIMP (hyper-methylated; #7) and LOW (hypo-methylated; #7), regardless of their E or non-E histotype. Integrated analyses of methylome and transcriptome data revealed that CIMP PM cells had a substantial number of hyper-methylated, silenced genes, which negatively impacted their immune phenotype compared to LOW PM cells. Treatment with DHA reverted the methylation-driven immune-compromised profile of CIMP PM cells and enhanced the constitutive immune-favorable profile of LOW PM cells.\u0000Conclusion: the study highlighted the relevance of DNA methylation in shaping the constitutive immune classification of PM cells, that is independent from their histological subtypes. The identified role of DHA in shifting the phenotype of PM cells towards an immune-favorable state supports its role in clinical trials of precision epigenetic therapy combined with ICI.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor localization strategies of multi-cancer early detection tests: a quantitative assessment","authors":"Christopher Tyson, Kevin H. Li, Xiting Cao, James M. O'Brien, Elliot K. Fishman, Elizabeth K. O'Donnell, Carlos Duran, Vijay Parthasarathy, Seema P. Rego, Omair A. Choudhry, Tomasz M. Beer","doi":"10.1101/2024.08.07.607020","DOIUrl":"https://doi.org/10.1101/2024.08.07.607020","url":null,"abstract":"Introduction\u0000Blood-based multi-cancer early detection (MCED) tests may expand the number of screenable cancers. Defining an optimal approach to diagnostic resolution for individuals with positive MCED test results is critical. Two prospective trials employed distinct diagnostic resolution approaches; one employed a molecular signal to predict tissue of origin (TOO) and the other used an imaging-based diagnostic strategy. Using mathematical modeling, we compared the diagnostic burden of each approach and characterized the risk of excess cancer incidence that may be attributable to radiation exposure associated with a false positive (FP) MCED test result and an imaging-based diagnostic strategy. Methods\u0000A mathematical expression for diagnostic burden was derived using MCED test positive predictive value (PPV), molecular TOO localization accuracy, and the expected number of imaging procedures associated with each diagnostic outcome. Imaging and molecular TOO strategies were compared by estimating diagnostic burden across a wide range of MCED PPVs and TOO accuracies. Organ-specific radiation dose for diagnostic imaging was extracted from the literature and used as input to National Cancer Institute RADRat tool for estimating excess lifetime cancer risk due to radiation exposure. Results\u0000For the molecular TOO diagnostic approach, an average of 2.1 procedures are required to reach diagnostic resolution for correctly-localized TPs, 4.4 procedures for incorrectly-localized TPs, and 4 procedures for FPs, vs. an average of 2.75 procedures for TPs and 2.4 for FPs with an imaging-based diagnostic strategy. Across the entire range of possible PPV and localization performance, a molecular TOO strategy resulted in a higher mean diagnostic burden: 3.6 procedures (SD 0.445) vs. 2.6 procedures (SD 0.1) for the imaging strategy. Predicted diagnostic burden was higher for molecular TOO in 95.5% of all possible PPV and TOO accuracy combinations; 79% or higher PPV would be required for a 90% accurate molecular TOO strategy to be less burdensome than imaging. The maximum rate of excess cancer incidence from radiation exposure for FP results from MCED screening between the ages of 50-84 was estimated at 64.6 per 100,000 (annual testing, 99% specificity), 48.5 per 100,000 (biennial testing, 98.5% specificity), and 64.6 per 100,000 (biennial testing, 98% specificity).\u0000Conclusions\u0000This analysis demonstrates that an imaging-based diagnostic strategy is more efficient than a molecular TOO-informed approach across 95.5% of all possible MCED PPV and TOO accuracy combinations. The use of an imaging-based approach for cancer localization can be efficient and low risk compared to a molecular-based approach.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity","authors":"Jillian S. Weissenrieder, Jessica Peura, Usha Paudel, Nikita Bhalerao, Natalie Weinmann, Calvin Johnson, Maximilian Wengyn, Rebecca Drager, Emma Elizabeth Furth, Karl Simin, Marcus Ruscetti, Ben Stanger, Anil K. Rustgi, Jason R. Pitarresi, J Kevin Foskett","doi":"10.1101/2024.08.08.607195","DOIUrl":"https://doi.org/10.1101/2024.08.08.607195","url":null,"abstract":"Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to- mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGFβ. Snail re-expression and TGFβ treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions between neutrophils and macrophages harboring gram-negative bacteria promote obesity-associated breast cancer","authors":"Sina T. Takle, Sturla Magnus Grondal, Martin E. Lien, Priscilia Lianto, Wei Deng, Reidun Kristine Lillestol, Per Lonning, James B. Lorens, Stian Knappskog, Nils Halberg","doi":"10.1101/2024.08.08.607253","DOIUrl":"https://doi.org/10.1101/2024.08.08.607253","url":null,"abstract":"Obesity promotes a more aggressive breast cancer phenotype. Through spatial and single-cell- based analysis of hormone receptor-negative breast cancers, we identify a subset of tumor- associated neutrophils (TANs) positive for granzyme B (GZMB) enriched in the tumor microenvironment of obese patients. In breast tumors evolved in obese environments, TANs are in proximity of M2 polarized macrophages containing lipopolysaccharides (LPS) from gram- negative bacteria. Pyroptosis of macrophages releases bacterial LPS, activating local GZMB+ TANs. This induces release of the S100 family member S100A8 that promotes tumor progression. In sum, we describe an obesity associated cellular network of cancer cells, neutrophils and M2 polarized macrophages that promotes tumor growth.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell multidimensional profiling of tumor cell heterogeneity in supratentorial ependymomas","authors":"Daeun Jeong, Sara G. Danielli, Kendra K. Maaß, David R. Ghasemi, Svenja K. Tetzlaff, Ekin Reyhan, Carlos Alberto Oliveira de Biagi-Junior, Sina Neyazi, Andrezza Nascimento, Rebecca Haase, Costanza Lo Cascio, Bernhard Englinger, Li Jiang, Cuong M. Nguyen, Alicia-Christina Baumgartner, Sophia Castellani, Jacob S. Rozowsky, Olivia A. Hack, McKenzie L. Shaw, Daniela Lotsch-Gojo, Katharina Bruckner, Stefan M. Pfister, Marcel Kool, Tomasz J. Nowakowski, Johannes Gojo, Lissa Baird, Sanda Alexandrescu, Kristian W. Pajtler, Varun Venkataramani, Mariella G. Filbin","doi":"10.1101/2024.08.07.607066","DOIUrl":"https://doi.org/10.1101/2024.08.07.607066","url":null,"abstract":"Supratentorial ependymomas are aggressive childhood brain cancers that retain features of neurodevelopmental cell types and segregate into molecularly and clinically distinct subgroups, suggesting different developmental roots. The developmental signatures as well as microenvironmental factors underlying aberrant cellular transformation and behavior across each supratentorial ependymoma subgroup are unknown. Here we integrated single cell- and spatial transcriptomics, as well as <em>in vitro</em> and <em>in vivo</em> live-cell imaging to define supratentorial ependymoma cell states, spatial organization, and dynamic behavior within the neural microenvironment. We find that individual tumor subgroups harbor two distinct progenitor-like cell states reminiscent of early human brain development and diverge in the extent of neuronal or ependymal differentiation. We further uncover several modes of spatial organization of these tumors, including a high order architecture influenced by mesenchymal and hypoxia signatures. Finally, we identify an unappreciated role for brain-resident cells in shifting supratentorial ependymoma cellular heterogeneity towards neuronal-like cells that co-opt immature neuronal morphology and invasion mechanisms. Collectively, these findings provide a multidimensional framework to integrate transcriptional and phenotypic characterization of tumor heterogeneity in supratentorial ependymoma and its potential clinical implications.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Composite impact of genome-wide APOBEC3-mediated mutations and HLA haplotype on cancer immunogenicity has a sex-biased survival impact","authors":"Faezeh Borzooee, Alireza Heravi-Moussavi, Mani Larijani","doi":"10.1101/2024.08.07.607038","DOIUrl":"https://doi.org/10.1101/2024.08.07.607038","url":null,"abstract":"APOBEC3A and APOBEC3B genome mutator enzymes drive tumor evolution and drug resistance. However, their mutational activity can also generate neoepitopes that activate cytotoxic T cells (CTLs). Given the high polymorphism of Class I HLA, the CTL immunopeptidome is individual-specific. We used a genome-wide immunogenicity scanning pipeline to assess how APOBEC3A/B-induced mutations affect the immunogenicity of the entire human immunopeptidome, consisting of all possible 8-11mer peptides restricted by several thousand HLA class I alleles. We evaluated several billion APOBEC3-mediated mutations for their potential to alter peptide:MHC and T cell receptor binding, either increasing or decreasing immunogenicity. We then ranked HLA alleles based on the degree to which their restricted immunopeptidome lost or gained immunogenicity when mutated by APOBEC3A or APOBEC3B. We found that HLA class I alleles vary infinitely in the proportions of their immunopeptidome whose immunogenicity is diminished vs. enhanced by APOBEC3-mediated mutations, with mutations in APOBEC3B hotspots having the greatest potential for enhancement of immunogenicity. The cumulative potential of an individual’s HLA haplotype’s immunopeptidome to gain or lose immunogenicity upon APOBEC3-mediated mutation predicts survival in APOBEC3-mutated tumors and correlates with increased CD8+ T cell activation. Thus, HLA haplotype is a prognostic marker in APOBEC3-mutated tumors.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep Visual Proteomics reveals DNA replication stress as a hallmark of Signet Ring Cell Carcinoma","authors":"Sonja Kabatnik, Xiang Zheng, Georgios Pappas, Sophia Steigerwald, Matthew P Padula, Matthias Mann","doi":"10.1101/2024.08.07.606985","DOIUrl":"https://doi.org/10.1101/2024.08.07.606985","url":null,"abstract":"Signet Ring Cell Carcinoma (SRCC) is a rare and highly malignant form of adenocarcinoma with increasing incidence and poor prognosis due to late diagnosis and limited treatment options. We employed Deep Visual Proteomics (DVP), which combines AI directed cell segmentation and classification with laser microdissection and ultra-high sensitivity mass spectrometry, for cell-type specific proteomic analysis of SRCC across the bladder, prostate, liver, and lymph nodes of a single patient. DVP identified significant alterations in DNA damage response (DDR) proteins, particularly within the ATR and mismatch repair (MMR) pathways, indicating replication stress as a crucial factor in SRCC mutagenicity. Additionally, we observed substantial enrichment of immune-related proteins, reflecting high levels of cytotoxic T lymphocyte infiltration and elevated PD-1 expression. These findings suggest that pembrolizumab immunotherapy may be more effective than conventional chemotherapy for this patient. Our results provide novel insights into the proteomic landscape of SRCC, identifying potential targets and open up for personalized therapeutic strategies in managing SRCC.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploit Spatially Resolved Transcriptomic Data to Infer Cellular Features from Pathology Imaging Data","authors":"Zhining Sui, Ziyi Li, Wei Sun","doi":"10.1101/2024.08.05.606654","DOIUrl":"https://doi.org/10.1101/2024.08.05.606654","url":null,"abstract":"Digital pathology is a rapidly advancing field where deep learning methods can be employed to extract meaningful imaging features. However, the efficacy of training deep learning models is often hindered by the scarcity of annotated pathology images, particularly images with detailed annotations for small image patches or tiles. To overcome this challenge, we propose an innovative approach that leverages paired spatially resolved transcriptomic data to annotate pathology images. We demonstrate the feasibility of this approach and introduce a novel transfer-learning neural network model, STpath (Spatial Transcriptomics and pathology images), designed to predict cell type proportions or classify tumor microenvironments. Our findings reveal that the features from pre-trained deep learning models are associated with cell type identities in pathology image patches. Evaluating STpath using three distinct breast cancer datasets, we observe its promising performance despite the limited training data. STpath excels in samples with variable cell type proportions and high-resolution pathology images. As the influx of spatially resolved transcriptomic data continues, we anticipate ongoing updates to STpath, evolving it into an invaluable AI tool for assisting pathologists in various diagnostic tasks.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MUC2 Expression Modulates Immune Infiltration in Colorectal Cancer","authors":"Christophe M. Raynaud, Ayesha Jabeen, Eiman I. Ahmed, Satanay Hubrack, Apryl Sanchez, Shimaa Sherif, Ahmad A Al-Shaibi, Jessica Roelands, Bernice Lo, Davide Bedognetti, Wouter Hendrickx","doi":"10.1101/2024.08.06.594842","DOIUrl":"https://doi.org/10.1101/2024.08.06.594842","url":null,"abstract":"<strong>Introduction</strong> Colorectal cancer (CRC) is a prevalent malignancy with significant morbidity and mortality worldwide. A deeper understanding of the interaction of cancer cells with other cells in the tumor microenvironment is crucial for devising effective therapeutic strategies. MUC2, a major component of the protective mucus layer in the gastrointestinal tract, has been implicated in CRC progression and immune response regulation.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The PVT1, HULC, and HOTTIP expression changes due to treatment in Diffuse Large B-cell lymphoma","authors":"Milad Shahsavari, Sedigheh Arbabian, Farzaneh Hosseini, Mohamad Reza Razavi","doi":"10.1101/2024.08.05.606587","DOIUrl":"https://doi.org/10.1101/2024.08.05.606587","url":null,"abstract":"Diffuse large B-cell lymphoma is the most common histological subtype of non-Hodgkin’s lymphomas. It is an aggressive malignancy that displays great heterogeneity in morphology, genetics, biological behavior and treatment response owing to chromatin remodeling and epigenetics.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141930908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}