Pub Date : 2024-08-09DOI: 10.1101/2024.08.08.607174
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
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. Methods: 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. Results: 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. Conclusion: 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.
{"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}
Pub Date : 2024-08-09DOI: 10.1101/2024.08.07.607020
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
Introduction Blood-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 A 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 For 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). Conclusions This 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.
导言基于血液的多癌症早期检测（MCED）可扩大可筛查癌症的数量。为MCED检测结果呈阳性的个体确定最佳诊断分辨率方法至关重要。两项前瞻性试验采用了不同的诊断分辨率方法；其中一项采用分子信号预测原发组织（TOO），另一项采用基于成像的诊断策略。通过数学建模，我们比较了每种方法的诊断负担，并描述了假阳性（FP）MCED 检测结果和基于成像的诊断策略可能导致的辐照引起的癌症发病率过高的风险。方法 利用 MCED 检测的阳性预测值 (PPV)、分子 TOO 定位的准确性以及与每种诊断结果相关的成像程序的预期次数，得出诊断负担的数学表达式。通过估算各种 MCED PPV 和 TOO 精确度的诊断负担，对成像和分子 TOO 策略进行了比较。从文献中提取了诊断成像的器官特异性辐射剂量，并将其作为国家癌症研究所 RADRat 工具的输入，用于估算辐射照射导致的终生超额癌症风险。结果对于分子 TOO 诊断方法，正确定位的 TPs 平均需要 2.1 次手术才能达到诊断分辨率，错误定位的 TPs 需要 4.4 次手术，FPs 需要 4 次手术，而采用基于成像的诊断策略，TPs 平均需要 2.75 次手术，FPs 平均需要 2.4 次手术。在可能的 PPV 和定位性能的整个范围内，分子 TOO 策略导致了更高的平均诊断负担：3.6 个手术（SD 0.445），而成像诊断策略为 2.6 个手术（SD 0.1）。在所有可能的 PPV 和 TOO 精确度组合中，95.5% 的分子 TOO 预测诊断负担较高；若分子 TOO 精确度达到 90%，则需要 79% 或更高的 PPV，诊断负担才会低于造影。据估计，在 50-84 岁年龄段的人群中，MCED 筛查得出的 FP 结果导致的癌症超额发病率最高为每 10 万人中 64.6 例（每年检测一次，特异性为 99%）、每 10 万人中 48.5 例（每两年检测一次，特异性为 98.5%）和每 10 万人中 64.6 例（每两年检测一次，特异性为 98%）。与基于分子的方法相比，使用基于成像的方法进行癌症定位既高效又低风险。
{"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}
Pub Date : 2024-08-09DOI: 10.1101/2024.08.08.607195
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
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.
{"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}
Pub Date : 2024-08-09DOI: 10.1101/2024.08.08.607253
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
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.
{"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}
Pub Date : 2024-08-09DOI: 10.1101/2024.08.07.607066
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
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 in vitro and in vivo 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.
{"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}
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.
APOBEC3A 和 APOBEC3B 基因组突变酶驱动肿瘤进化和耐药性。然而，它们的突变活性也能产生激活细胞毒性 T 细胞（CTL）的新表位。鉴于 I 类 HLA 的高度多态性，CTL 免疫肽组具有个体特异性。我们使用全基因组免疫原性扫描管道来评估 APOBEC3A/B 诱导的突变如何影响整个人类免疫肽组的免疫原性，该免疫肽组由数千个 HLA I 类等位基因限制的所有可能的 8-11mer 肽组成。我们评估了数十亿个 APOBEC3 介导的突变，看它们是否可能改变肽与 MHC 和 T 细胞受体的结合，从而增加或减少免疫原性。然后，我们根据其受限免疫肽组在 APOBEC3A 或 APOBEC3B 突变时失去或获得免疫原性的程度对 HLA 等位基因进行了排序。我们发现，HLA I 类等位基因在其免疫肽组中因 APOBEC3 介导的突变而降低或增强免疫原性的比例存在无限差异，其中 APOBEC3B 热点突变增强免疫原性的潜力最大。个体的 HLA 单倍型免疫肽组在 APOBEC3 介导的突变后获得或丧失免疫原性的累积潜力可预测 APOBEC3 突变肿瘤的存活率，并与 CD8+ T 细胞活化的增加相关。因此，HLA单倍型是APOBEC3突变肿瘤的预后标志物。
{"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}
Pub Date : 2024-08-08DOI: 10.1101/2024.08.07.606985
Sonja Kabatnik, Xiang Zheng, Georgios Pappas, Sophia Steigerwald, Matthew P Padula, Matthias Mann
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.
{"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}
Pub Date : 2024-08-07DOI: 10.1101/2024.08.05.606654
Zhining Sui, Ziyi Li, Wei Sun
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.
{"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}
Pub Date : 2024-08-07DOI: 10.1101/2024.08.06.594842
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
Introduction 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.
{"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}
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.
{"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}
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