Analyses of Transcriptomics Cell Signalling for Pre-Screening Applications in the Integrated Approach for Testing and Assessment of Non-Genotoxic Carcinogens
Abstract
:1. Introduction
2. Transcriptomics to Predict Mechanisms of Action of Non-Genotoxic Carcinogens
- the gene panels and assays (Section 3)
- the cells or tissues; (Section 4.1)
- the time points and concentrations or doses (Section 4.2)
- the derivation of points of departure for human risk assessment purposes (Section 4.3)
3. Transcriptomic Assays and Gene Panels to Identify Key Cell Signalling Pathways and Predictive Markers
3.1. Classification Systems and Assays
3.2. Rodent and Human Biomarker in Carcinogenicity Studies
3.3. Example of a Tool for Pre-Screening the Gene Expression Changes Associated Carcinogenic Phenotypes
4. Critical Elements to Include When Designing Transcriptomic Testing Combinations
4.1. Prioritisation of Cell Types and Cell Lines to Be Used in Transcriptomic Assays
4.2. Duration of Chemical Exposure and Concentration/Dose Selection
4.3. Threshold Development for the Gene Expression Assay
4.4. Tools to Identify Potential Reference Chemicals
4.5. Proposed Key Omics Markers for Inclusion in the NGTxC IATA
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Cieślik, M.; Chinnaiyan, A.M. Cancer transcriptome profiling at the juncture of clinical translation. Nat. Rev. Genet. 2018, 19, 93–109. [Google Scholar] [CrossRef] [PubMed]
- Bailey, M.H.; Tokheim, C.; Porta-Pardo, E.; Sengupta, S.; Bertrand, D.; Weerasinghe, A.; Colaprico, A.; Wendl, M.C.; Kim, J.; Reardon, B.; et al. Comprehensive Characterization of Cancer Driver Genes and Mutations. Cell 2018, 173, 371–385.E18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Berger, A.C.; Korkut, A.; Kanchi, R.S.; Hegde, A.M.; Lenoir, W.; Liu, W.; Liu, Y.; Fan, H.; Shen, H.; Ravikumar, V.; et al. A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers. Cancer Cell 2018, 33, 690–705.e9. [Google Scholar] [CrossRef] [Green Version]
- Campbell, J.D.; Yau, C.; Bowlby, R.; Liu, Y.; Brennan, K.; Fan, H.; Taylor, A.M.; Wang, C.; Walter, V.; Akbani, R.; et al. Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas. Cell Rep. 2018, 23, 194–212.e6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kahles, A.; Lehmann, K.-V.; Toussaint, N.C.; Hüser, M.; Stark, S.G.; Sachsenberg, T.; Stegle, O.; Kohlbacher, O.; Sander, C.; Caesar-Johnson, S.J.; et al. Comprehensive Analysis of Alternative Splicing Across Tumors from 8705 Patients. Cancer Cell 2018, 34, 211–224.e6. [Google Scholar] [CrossRef] [Green Version]
- Gao, Q.; Liang, W.-W.; Foltz, S.M.; Mutharasu, G.; Jayasinghe, R.G.; Cao, S.; Liao, W.-W.; Reynolds, S.M.; Wyczalkowski, M.A.; Yao, L.; et al. Driver Fusions and Their Implications in the Development and Treatment of Human Cancers. Cell Rep. 2018, 23, 227–238.e223. [Google Scholar] [CrossRef] [Green Version]
- Ding, L.; Bailey, M.H.; Porta-Pardo, E.; Thorsson, V.; Colaprico, A.; Bertrand, D.; Gibbs, D.L.; Weerasinghe, A.; Huang, K.-L.; Tokheim, C.; et al. Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics. Cell 2018, 173, 305–320.e10. [Google Scholar] [CrossRef] [Green Version]
- Liu, Y.; Sethi, N.S.; Hinoue, T.; Schneider, B.G.; Cherniack, A.D.; Sanchez-Vega, F.; Seoane, J.A.; Farshidfar, F.; Bowlby, R.; Islam, M.; et al. Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas. Cancer Cell 2018, 33, 721–735.e8. [Google Scholar] [CrossRef] [Green Version]
- Ricketts, C.J.; De Cubas, A.A.; Fan, H.; Smith, C.C.; Lang, M.; Reznik, E.; Bowlby, R.; Gibb, E.A.; Akbani, R.; Beroukhim, R.; et al. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma. Cell Rep. 2018, 23, 313–326.e5. [Google Scholar] [CrossRef] [Green Version]
- Hoadley, K.A.; Yau, C.; Hinoue, T.; Wolf, D.M.; Lazar, A.J.; Drill, E.; Shen, R.; Taylor, A.M.; Cherniack, A.D.; Thorsson, V.; et al. Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer. Cell 2018, 173, 291–304.e296. [Google Scholar] [CrossRef]
- Luch, A. Nature and nurture–lessons from chemical carcinogenesis. Nat. Rev. Cancer 2005, 5, 113–125. [Google Scholar] [CrossRef] [PubMed]
- Jacobs, M.N.; Colacci, A.; Corvi, R.; Vaccari, M.; Aguila, M.C.; Corvaro, M.; Delrue, N.; Desaulniers, D.; Ertych, N.; Jacobs, A.; et al. Chemical carcinogen safety testing: OECD expert group international consensus on the development of an integrated approach for the testing and assessment of chemical non-genotoxic carcinogens. Arch. Toxicol. 2020, 94, 2899–2923. [Google Scholar] [CrossRef] [PubMed]
- Adler, S.; Basketter, D.; Creton, S.; Pelkonen, O.; Van Benthem, J.; Zuang, V.; Andersen, K.E.; Angers-Loustau, A.; Aptula, A.; Bal-Price, A.; et al. Alternative (non-animal) methods for cosmetics testing: Current status and future Current Status and Future Prospects-2010. Arch. Toxicol. 2011, 85, 367–485. [Google Scholar] [CrossRef] [PubMed]
- Cimino, M.C. Comparative overview of current international strategies and guidelines for genetic toxicology testing for regulatory purposes. Environ. Mol. Mutagen. 2006, 47, 362–390. [Google Scholar] [CrossRef]
- Pistollato, F.; Madia, F.; Corvi, R.; Munn, S.; Grignard, E.; Paini, A.; Worth, A.; Bal-Price, A.; Prieto, P.; Casati, S.; et al. Current EU Regulatory Requirements for the Assessment of Chemicals and Cosmetic Products: Challenges and Opportunities for In-troducing New Approach Methodologies. Arch Toxicol 2021, 95. [Google Scholar] [CrossRef]
- Luijten, M.; Olthof, E.D.; Hakkert, B.C.; Rorije, E.; van der Laan, J.-W.; Woutersen, R.A.; van Benthem, J. An integrative test strategy for cancer hazard identification. Crit. Rev. Toxicol. 2016, 46, 615–639. [Google Scholar] [CrossRef]
- Corvi, R.; Madia, F. In vitro genotoxicity testing–Can the performance be enhanced? Food Chem. Toxicol. 2017, 106, 600–608. [Google Scholar] [CrossRef]
- Jacobs, M.N.; Colacci, A.; Louekari, K.; Luijten, M.; Hakkert, B.C.; Paparella, M.; Vasseur, P. International regulatory needs for development of an IATA for non-genotoxic carcinogenic chemical substances. ALTEX 2016, 33, 359–392. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hanahan, D.; Weinberg, R.A. Hallmarks of Cancer: The Next Generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [Green Version]
- Smith, M.T.; Guyton, K.Z.; Gibbons, C.F.; Fritz, J.; Portier, C.; Rusyn, I.; DeMarini, D.; Caldwell, J.C.; Kavlock, R.J.; Lambert, P.F.; et al. Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis. Environ. Health Perspect. 2016, 124, 713–721. [Google Scholar] [CrossRef]
- Aardema, M.J.; MacGregor, J.T. Toxicology and genetic toxicology in the new era of “toxicogenomics”: Impact of “-omics” technologies. Mutat. Res. Fundam. Mol. Mech. Mutagen. 2002, 499, 13–25. [Google Scholar] [CrossRef]
- David, R. The promise of toxicogenomics for genetic toxicology: Past, present and future. Mutagenesis 2020, 35, 153–159. [Google Scholar] [CrossRef] [PubMed]
- Harrill, J.A.; Viant, M.R.; Yauk, C.L.; Sachana, M.; Gant, T.W.; Auerbach, S.S.; Beger, R.D.; Bouhifd, M.; O’Brien, J.; Burgoon, L.; et al. Progress towards an OECD reporting framework for transcriptomics and metabolomics in regulatory toxicology. Regul. Toxicol. Pharmacol. 2021, 125, 105020. [Google Scholar] [CrossRef]
- Verheijen, M.; Tong, W.; Shi, L.; Gant, T.W.; Seligman, B.; Caiment, F. Towards the development of an omics data analysis framework. Regul. Toxicol. Pharmacol. 2020, 112, 104621. [Google Scholar] [CrossRef] [PubMed]
- Dean, J.L.; Zhao, Q.J.; Lambert, J.C.; Hawkins, B.S.; Thomas, R.S.; Wesselkamper, S.C. Application of Gene Set Enrichment Analysis for Identification of Chemically Induced, Biologically Relevant Transcriptomic Networks and Potential Utilization in Human Health Risk Assessment. Toxicol. Sci. 2017, 157, 85–99. [Google Scholar] [CrossRef] [PubMed]
- Subramanian, A.; Tamayo, P.; Mootha, V.K.; Mukherjee, S.; Ebert, B.L.; Gillette, M.A.; Paulovich, A.; Pomeroy, S.L.; Golub, T.R.; Lander, E.S.; et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 2005, 102, 15545–15550. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gao, C.; Weisman, D.; Lan, J.; Gou, N.; Gu, A.Z. Toxicity Mechanisms Identification via Gene Set Enrichment Analysis of Time-Series Toxicogenomics Data: Impact of Time and Concentration. Environ. Sci. Technol. 2015, 49, 4618–4626. [Google Scholar] [CrossRef] [PubMed]
- Pendse, S.N.; Maertens, A.; Rosenberg, M.; Roy, D.; Fasani, R.A.; Vantangoli, M.M.; Madnick, S.J.; Boekelheide, K.; Fornace, A.J.; Odwin, S.-A.; et al. Information-dependent enrichment analysis reveals time-dependent transcriptional regulation of the estrogen pathway of toxicity. Arch. Toxicol. 2016, 91, 1749–1762. [Google Scholar] [CrossRef] [Green Version]
- Aguayo-Orozco, A.; Bois, F.Y.; Brunak, S.; Taboureau, O. Analysis of Time-Series Gene Expression Data to Explore Mechanisms of Chemical-Induced Hepatic Steatosis Toxicity. Front. Genet. 2018, 9, 396. [Google Scholar] [CrossRef]
- Mascolo, M.G.; Perdichizzi, S.; Vaccari, M.; Rotondo, F.; Zanzi, C.; Grilli, S.; Paparella, M.; Jacobs, M.N.; Colacci, A. The transformics assay: First steps for the development of an integrated approach to investigate the malignant cell transformation in vitro. Carcinogenesis 2018, 39, 955–967. [Google Scholar] [CrossRef]
- Pillo, G.; Mascolo, M.G.; Zanzi, C.; Rotondo, F.; Serra, S.; Bortone, F.; Grilli, S.; Vaccari, M.; Jacobs, M.N.; Colacci, A. Mechanistic Interrogation of Cell Transformation In Vitro: The Transformics Assay as an Exemplar of Oncotransformation. Int. J. Mol. Sci. 2022, 23, 7603. [Google Scholar] [CrossRef] [PubMed]
- Ohmori, K.; Kamei, A.; Watanabe, Y.; Abe, K. Gene Expression over Time during Cell Transformation Due to Non-Genotoxic Carcinogen Treatment of Bhas 42 Cells. Int. J. Mol. Sci. 2022, 23, 3216. [Google Scholar] [CrossRef] [PubMed]
- Mi, H.; Ebert, D.; Muruganujan, A.; Mills, C.; Albou, L.-P.; Mushayamaha, T.; Thomas, P.D. PANTHER version 16: A revised family classification, tree-based classification tool, enhancer regions and extensive API. Nucleic Acids Res. 2020, 49, D394–D403. [Google Scholar] [CrossRef] [PubMed]
- Mi, H.; Muruganujan, A.; Ebert, D.; Huang, X.; Thomas, P.D. PANTHER version 14: More genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucleic Acids Res. 2018, 47, D419–D426. [Google Scholar] [CrossRef]
- Gaudet, P.; Livstone, M.S.; Lewis, S.E.; Thomas, P.D. Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Brief. Bioinform. 2011, 12, 449–462. [Google Scholar] [CrossRef] [Green Version]
- Romanov, S.; Medvedev, A.; Gambarian, M.; Poltoratskaya, N.; Moeser, M.; Medvedeva, L.; Gambarian, M.; Diatchenko, L.; Makarov, S.S. Homogeneous reporter system enables quantitative functional assessment of multiple transcription factors. Nat. Methods 2008, 5, 253–260. [Google Scholar] [CrossRef]
- Grashow, R.G.; De La Rosa, V.Y.; Watford, S.; Ackerman, J.M.; Rudel, R.A. BCScreen: A gene panel to test for breast carcinogenesis in chemical safety screening. Comput. Toxicol. 2017, 5, 16–24. [Google Scholar] [CrossRef] [Green Version]
- Sanchez-Vega, F.; Mina, M.; Armenia, J.; Chatila, W.K.; Luna, A.; La, K.C.; Dimitriadoy, S.; Liu, D.L.; Kantheti, H.S.; Saghafinia, S.; et al. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell 2018, 173, 321–337.e310. [Google Scholar] [CrossRef] [Green Version]
- Corton, J.C.; Hill, T.; Sutherland, J.J.; Stevens, J.L.; Rooney, J. A Set of Six Gene Expression Biomarkers Identify Rat Liver Tumorigens in Short-term Assays. Toxicol. Sci. 2020, 177, 11–26. [Google Scholar] [CrossRef] [PubMed]
- Callegaro, G.; Kunnen, S.J.; Trairatphisan, P.; Grosdidier, S.; Niemeijer, M.; Hollander, W.D.; Guney, E.; Gonzalez, J.P.; Furlong, L.; Webster, Y.W.; et al. The Human Hepatocyte TXG-MAPr: Gene Co-Expression Network Modules to Support Mechanism-Based Risk Assessment. Arch. Toxicol. 2021, 95, 3745–3775. [Google Scholar] [CrossRef]
- McMullen, P.D.; Pendse, S.N.; Black, M.B.; Mansouri, K.; Haider, S.; Andersen, M.E.; Clewell, R.A. Addressing systematic inconsistencies between in vitro and in vivo transcriptomic mode of action signatures. Toxicol. Vitr. 2019, 58, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Luijten, M.; Wackers, P.F.K.; Rorije, E.; Pennings, J.L.A.; Heusinkveld, H.J. Relevance of In Vitro Transcriptomics for In Vivo Mode of Action Assessment. Chem. Res. Toxicol. 2020, 34, 452–459. [Google Scholar] [CrossRef] [PubMed]
- Liu, Z.; Fang, H.; Borlak, J.; Roberts, R.; Tong, W. In vitro to in vivo extrapolation for drug-induced liver injury using a pair ranking method_suppl. ALTEX 2017, 34, 399–407. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grinberg, M.; Stöber, R.M.; Albrecht, W.; Edlund, K.; Schug, M.; Godoy, P.; Cadenas, C.; Marchan, R.; Lampen, A.; Braeuning, A.; et al. Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes. Arch. Toxicol. 2018, 92, 3517–3533. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- El-Hachem, N.; Grossmann, P.; Blanchet-Cohen, A.; Bateman, A.R.; Bouchard, N.; Archambault, J.; Aerts, H.J.W.L.; Haibe-Kains, B. Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms. Environ. Health Perspect. 2016, 124, 313–320. [Google Scholar] [CrossRef] [Green Version]
- Tucker, D.K.; Bouknight, S.H.; Brar, S.S.; Kissling, G.E.; Fenton, S.E. Evaluation of Prenatal Exposure to Bisphenol Analogues on Development and Long-Term Health of the Mammary Gland in Female Mice. Environ. Health Perspect. 2018, 126, 087003. [Google Scholar] [CrossRef] [Green Version]
- Davis, B.; Fenton, S. Chapter 61–Mammary Gland. In Haschek and Rousseaux’s Handbook of Toxicologic Pathology; Academic Press: Cambridge, MA, USA, 2013. [Google Scholar]
- Filgo, A.J.; Foley, J.F.; Puvanesarajah, S.; Borde, A.R.; Midkiff, B.R.; Reed, C.E.; Chappell, V.A.; Alexander, L.B.; Borde, P.R.; Troester, M.A.; et al. Mammary Gland Evaluation in Juvenile Toxicity Studies: Temporal Developmental Patterns in the Male and Female Harlan Sprague-Dawley Rat. Toxicol. Pathol. 2016, 44, 1034–1058. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Duderstadt, E.L.; Sanders, M.A.; Samuelson, D.J. A Method to Pre-Screen Rat Mammary Gland Whole-Mounts Prior To RNAscope. J. Mammary Gland Biol. Neoplasia 2021, 26, 113–120. [Google Scholar] [CrossRef]
- Nik-Zainal, S.; Van Loo, P.; Wedge, D.C.; Alexandrov, L.B.; Greenman, C.D.; Lau, K.W.; Raine, K.; Jones, D.; Marshall, J.; Ramakrishna, M.; et al. The Life History of 21 Breast Cancers. Cell 2012, 149, 994–1007. [Google Scholar] [CrossRef] [Green Version]
- Wang, D.-Y.; Jiang, Z.; Ben-David, Y.; Woodgett, J.R.; Zacksenhaus, E. Molecular stratification within triple-negative breast cancer subtypes. Sci. Rep. 2019, 9, 19107. [Google Scholar] [CrossRef]
- Liberzon, A.; Subramanian, A.; Pinchback, R.; Thorvaldsdóttir, H.; Tamayo, P.; Mesirov, J.P. Molecular signatures database (MSigDB) 3. Bioinformatics 2011, 27, 1739–1740. [Google Scholar] [CrossRef] [PubMed]
- Gao, S.; Gang, J.; Yu, M.; Xin, G.; Tan, H. Computational analysis for identification of early diagnostic biomarkers and prognostic biomarkers of liver cancer based on GEO and TCGA databases and studies on pathways and biological functions affecting the survival time of liver cancer. BMC Cancer 2021, 21, 791. [Google Scholar] [CrossRef] [PubMed]
- Sun, X.; Zhou, Z.-R.; Fang, Y.; Ding, S.; Lu, S.; Wang, Z.; Wang, H.; Chen, X.; Shen, K. A novel metabolic gene signature-based nomogram to predict overall survival in breast cancer. Ann. Transl. Med. 2021, 9, 367. [Google Scholar] [CrossRef] [PubMed]
- Berglund, A.; Rounbehler, R.J.; Gerke, T.; Awasthi, S.; Cheng, C.-H.; Takhar, M.; Davicioni, E.; Alshalalfa, M.; Erho, N.; Klein, E.A.; et al. Distinct transcriptional repertoire of the androgen receptor in ETS fusion-negative prostate cancer. Prostate Cancer Prostatic Dis. 2018, 22, 292–302. [Google Scholar] [CrossRef]
- Chaurasiya, S.; Widmann, S.; Botero, C.; Lin, C.-Y.; Gustafsson, J.; Strom, A.M. Estrogen receptor β exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity. PLoS ONE 2020, 15, e0226057. [Google Scholar] [CrossRef]
- Yang, Y.; Chen, L.; Xu, X.; Fan, Z.; Li, W.; Niu, C. Identification of Therapeutic Targets of Breast Cancer. Int. J. Clin. Exp. Med. 2016, 9, 1789–1795. [Google Scholar]
- de Galarreta, M.R.; Bresnahan, E.; Molina-Sánchez, P.; Lindblad, K.E.; Maier, B.; Sia, D.; Puigvehi, M.; Miguela, V.; Casanova-Acebes, M.; Dhainaut, M.; et al. β-Catenin Activation Promotes Immune Escape and Resistance to Anti–PD-1 Therapy in Hepatocellular Carcinoma. Cancer Discov. 2019, 9, 1124–1141. [Google Scholar] [CrossRef]
- Gong, Y.; Wei, Z. Identification of PSMD14 as a potential novel prognosis biomarker and therapeutic target for osteosarcoma. Cancer Rep. 2021, 5, e1522. [Google Scholar] [CrossRef]
- Yang, J.; Min, K.-W.; Kim, N.-H.; Son, B.K.; Moon, K.M.; Wi, Y.C.; Bang, S.S.; Oh, Y.H.; Do, S.-I.; Chae, S.W.; et al. High TNFRSF12A level associated with MMP-9 overexpression is linked to poor prognosis in breast cancer: Gene set enrichment analysis and validation in large-scale cohorts. PLoS ONE 2018, 13, e0202113. [Google Scholar] [CrossRef]
- Liu, D.; Xu, X.; Wen, J.; Xie, L.; Zhang, J.; Shen, Y.; Jiang, G.; Chen, J.; Fan, M. Integrated Genome-Wide Analysis of Gene Expression and DNA Copy Number Variations Highlights Stem Cell-Related Pathways in Small Cell Esophageal Carcinoma. Stem Cells Int. 2018, 2018, 3481783. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huang, X.; Yan, J.; Zhang, M.; Wang, Y.; Chen, Y.; Fu, X.; Wei, R.; Zheng, X.-L.; Liu, Z.; Zhang, X.; et al. Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors. Cell 2018, 175, 186–199.e19. [Google Scholar] [CrossRef]
- Duan, W.; Jin, X.; Li, Q.; Tashiro, S.-I.; Onodera, S.; Ikejima, T. Silibinin Induced Autophagic and Apoptotic Cell Death in HT1080 Cells Through a Reactive Oxygen Species Pathway. J. Pharmacol. Sci. 2010, 113, 48–56. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Qian, Z.; Zhou, T.; Gurguis, C.I.; Xu, X.; Wen, Q.; Lv, J.; Fang, F.; Hecker, L.; Cress, A.; Natarajan, V.; et al. Nuclear factor, erythroid 2-like 2-associated molecular signature predicts lung cancer survival. Sci. Rep. 2015, 5, 16889. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Couturier, C.P.; Ayyadhury, S.; Le, P.U.; Nadaf, J.; Monlong, J.; Riva, G.; Allache, R.; Baig, S.; Yan, X.; Bourgey, M.; et al. Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy. Nat. Commun. 2020, 11, 3406. [Google Scholar] [CrossRef] [PubMed]
- Fernandez-Cuesta, L.; Peifer, M.; Lu, X.; Sun, R.; Ozretić, L.; Seidel, D.; Zander, T.; Leenders, F.; George, J.; Müller, C.; et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat. Commun. 2014, 5, 3518. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kondo, S.; Ota, A.; Ono, T.; Karnan, S.; Wahiduzzaman; Hyodo, T.; Rahman, L.; Ito, K.; Furuhashi, A.; Hayashi, T.; et al. Discovery of novel molecular characteristics and cellular biological properties in ameloblastoma. Cancer Med. 2020, 9, 2904–2917. [Google Scholar] [CrossRef] [Green Version]
- Chen, J.; Li, L.; Sun, L.; Yuan, Y.; Jing, J. Associations of individual and joint expressions of ERCC6 and ERCC8 with clinicopathological parameters and prognosis of gastric cancer. PeerJ 2021, 9, e11791. [Google Scholar] [CrossRef]
- Wang, H.; Hou, W.; Perera, A.; Bettler, C.; Beach, J.R.; Ding, X.; Li, J.; Denning, M.F.; Dhanarajan, A.; Cotler, S.J.; et al. Targeting EphA2 suppresses hepatocellular carcinoma initiation and progression by dual inhibition of JAK1/STAT3 and AKT signaling. Cell Rep. 2021, 34, 108765. [Google Scholar] [CrossRef]
- Sun, G.; Cheng, Y.-W.; Lai, L.; Huang, T.-C.; Wang, J.; Wu, X.; Wang, Y.; Huang, Y.; Wang, J.; Zhang, K.; et al. Signature miRNAs in colorectal cancers were revealed using a bias reduction small RNA deep sequencing protocol. Oncotarget 2015, 7, 3857–3872. [Google Scholar] [CrossRef] [Green Version]
- Decock, A.; Ongenaert, M.; De Wilde, B.; Brichard, B.; Noguera, R.; Speleman, F.; Vandesompele, J. Stage 4S neuroblastoma tumors show a characteristic DNA methylation portrait. Epigenetics 2016, 11, 761–771. [Google Scholar] [CrossRef] [Green Version]
- Moharram, S.A.; Shah, K.; Kazi, J.U. T-cell Acute Lymphoblastic Leukemia Cells Display Activation of Different Survival Pathways. J. Cancer 2017, 8, 4124. [Google Scholar] [CrossRef]
- Porrello, A.; Piergentili, R.B. Contextualizing the Genes Altered in Bladder Neoplasms in Pediatric and Teen Patients Allows Identifying Two Main Classes of Biological Processes Involved and New Potential Therapeutic Targets. Curr. Genom. 2015, 17, 33–61. [Google Scholar] [CrossRef] [Green Version]
- Zhao, Z.; Szczepanski, A.P.; Tsuboyama, N.; Abdala-Valencia, H.; Goo, Y.A.; Singer, B.D.; Bartom, E.T.; Yue, F.; Wang, L. PAX9 Determines Epigenetic State Transition and Cell Fate in Cancer. Cancer Res. 2021, 81, 4696–4708. [Google Scholar] [CrossRef]
- Phatak, A.; Athar, M.; Crowell, J.A.; Leffel, D.; Herbert, B.-S.; Bale, A.E.; Kopelovich, L. Global gene expression of histologically normal primary skin cells from BCNS subjects reveals “single-hit” effects that are influenced by rapamycin. Oncotarget 2019, 10, 1360–1387. [Google Scholar] [CrossRef] [Green Version]
- Pan, Z.; He, Y.; Zhu, W.; Xu, T.; Hu, X.; Huang, P. A Dynamic Transcription Factor Signature Along the Colorectal Adenoma-Carcinoma Sequence in Patients With Co-Occurrent Adenoma and Carcinoma. Front. Oncol. 2021, 11, 597449. [Google Scholar] [CrossRef]
- Marx, A.; Schumann, A.; Höflmayer, D.; Bady, E.; Hube-Magg, C.; Möller, K.; Tsourlakis, M.C.; Steurer, S.; Büscheck, F.; Eichenauer, T.; et al. Up regulation of the Hippo signalling effector YAP1 is linked to early biochemical recurrence in prostate cancers. Sci. Rep. 2020, 10, 8916. [Google Scholar] [CrossRef]
- Palomo-Irigoyen, M.; Pérez-Andrés, E.; Iruarrizaga-Lejarreta, M.; Barreira-Manrique, A.; Tamayo-Caro, M.; Vila-Vecilla, L.; Moreno-Cugnon, L.; Beitia, N.; Medrano, D.; Fernández-Ramos, D.; et al. HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis. J. Clin. Investig. 2020, 130, 3848–3864. [Google Scholar] [CrossRef] [Green Version]
- Shah, K.; Ahmed, M.; Kazi, J.U. The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia. npj Precis. Oncol. 2021, 5, 13. [Google Scholar] [CrossRef]
- Harada, M.; Morikawa, M.; Ozawa, T.; Kobayashi, M.; Tamura, Y.; Takahashi, K.; Tanabe, M.; Tada, K.; Seto, Y.; Miyazono, K.; et al. Palbociclib enhances activin-SMAD-induced cytostasis in estrogen receptor-positive breast cancer. Cancer Sci. 2018, 110, 209–220. [Google Scholar] [CrossRef]
- Xu, X.; Liu, T.; Wang, Y.; Fu, J.; Yang, Q.; Wu, J.; Zhou, H. miRNA–mRNA Associated With Survival in Endometrial Cancer. Front. Genet. 2019, 10, 743. [Google Scholar] [CrossRef] [Green Version]
- Shivarov, V.; Dolnik, A.; Lang, K.M.; Krönke, J.; Kuchenbauer, F.; Paschka, P.; Gaidzik, V.I.; Döhner, H.; Schlenk, R.F.; Döhner, K.; et al. MicroRNA expression-based outcome prediction in acute myeloid leukemia: Novel insights through cross-platform integrative analyses. Haematologica 2016, 101, e454–e456. [Google Scholar] [CrossRef]
- Labbé, D.P.; Sweeney, C.J.; Brown, M.; Galbo, P.; Rosario, S.; Wadosky, K.M.; Ku, S.-Y.; Sjöström, M.; Alshalalfa, M.; Erho, N.; et al. TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup. Clin. Cancer Res. 2017, 23, 7072–7083. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, J.-Q.; Liao, X.-W.; Wang, X.-K.; Yang, C.-K.; Zhou, X.; Liu, Z.-Q.; Han, Q.-F.; Fu, T.-H.; Zhu, G.-Z.; Han, C.-Y.; et al. Prognostic value of Glypican family genes in early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy and possible mechanisms. BMC Gastroenterol. 2020, 20, 415. [Google Scholar] [CrossRef] [PubMed]
- Cook, D.P.; Vanderhyden, B.C. Context specificity of the EMT transcriptional response. Nat. Commun. 2020, 11, 2142. [Google Scholar] [CrossRef]
- Ren, J.; Ward, D.; Chen, S.; Tran, K.; Jin, P.; Sabatino, M.; Robey, P.G.; Stroncek, D.F. Comparison of human bone marrow stromal cells cultured in human platelet growth factors and fetal bovine serum. J. Transl. Med. 2018, 16, 65. [Google Scholar] [CrossRef] [Green Version]
- Wang, Z.; Wang, Y.; Peng, M.; Yi, L. UBASH3B Is a Novel Prognostic Biomarker and Correlated With Immune Infiltrates in Prostate Cancer. Front. Oncol. 2020, 9, 1517. [Google Scholar] [CrossRef] [Green Version]
- Swerev, T.M.; Wirth, T.; Ushmorov, A. Activation of oncogenic pathways in classical Hodgkin lymphoma by decitabine: A rationale for combination with small molecular weight inhibitors. Int. J. Oncol. 2016, 50, 555–566. [Google Scholar] [CrossRef] [Green Version]
- Kocabayoglu, P.; Lade, A.; Lee, Y.A.; Dragomir, A.-C.; Sun, X.; Fiel, M.I.; Thung, S.; Aloman, C.; Soriano, P.; Hoshida, Y.; et al. β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J. Hepatol. 2015, 63, 141–147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Oshi, M.; Kim, T.; Tokumaru, Y.; Yan, L.; Matsuyama, R.; Endo, I.; Cherkassky, L.; Takabe, K. Enhanced DNA Repair Pathway is Associated with Cell Proliferation and Worse Survival in Hepatocellular Carcinoma (HCC). Cancers 2021, 13, 323. [Google Scholar] [CrossRef]
- Yin, L.; Chang, C.; Xu, C. G2/M checkpoint plays a vital role at the early stage of HCC by analysis of key pathways and genes. Oncotarget 2017, 8, 76305–76317. [Google Scholar] [CrossRef] [Green Version]
- Oshi, M.; Tokumaru, Y.; Angarita, F.A.; Lee, L.; Yan, L.; Matsuyama, R.; Endo, I.; Takabe, K. Adipogenesis in triple-negative breast cancer is associated with unfavorable tumor immune microenvironment and with worse survival. Sci. Rep. 2021, 11, 12541. [Google Scholar] [CrossRef] [PubMed]
- Goto, N.; Fukuda, A.; Yamaga, Y.; Yoshikawa, T.; Maruno, T.; Maekawa, H.; Inamoto, S.; Kawada, K.; Sakai, Y.; Miyoshi, H.; et al. Lineage tracing and targeting of IL17RB+ tuft cell-like human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA 2019, 116, 12996–13005. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hu, M.; Fu, X.; Si, Z.; Li, C.; Sun, J.; Du, X.; Zhang, H. Identification of Differently Expressed Genes Associated With Prognosis and Growth in Colon Adenocarcinoma Based on Integrated Bioinformatics Analysis. Front. Genet. 2019, 10, 1245. [Google Scholar] [CrossRef] [Green Version]
- Wang, W.; Wei, J.; Zhang, H.; Zheng, X.; Zhou, H.; Luo, Y.; Yang, J.; Deng, Q.; Huang, S.; Fu, Z. PRDX2 promotes the proliferation of colorectal cancer cells by increasing the ubiquitinated degradation of p53. Cell Death Dis. 2021, 12, 605. [Google Scholar] [CrossRef]
- Gehren, A.S.; Rocha, M.R.; De Souza, W.F.; Morgado-Díaz, J.A. Alterations of the apical junctional complex and actin cytoskeleton and their role in colorectal cancer progression. Tissue Barriers 2015, 3, e1017688. [Google Scholar] [CrossRef] [Green Version]
- Guo, C.; Xu, L.-F.; Li, H.-M.; Wang, W.; Guo, J.-H.; Jia, M.-Q.; Jia, R.; Jia, J. Transcriptomic study of the mechanism of anoikis resistance in head and neck squamous carcinoma. PeerJ 2019, 7, e6978. [Google Scholar] [CrossRef] [Green Version]
- Oshi, M.; Newman, S.; Tokumaru, Y.; Yan, L.; Matsuyama, R.; Endo, I.; Nagahashi, M.; Takabe, K. Intra-Tumoral Angiogenesis Is Associated with Inflammation, Immune Reaction and Metastatic Recurrence in Breast Cancer. Int. J. Mol. Sci. 2020, 21, 6708. [Google Scholar] [CrossRef]
- Desaulniers, D.; Vasseur, P.; Jacobs, A.; Aguila, M.C.; Ertych, N.; Jacobs, M.N. Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications. Int. J. Mol. Sci. 2021, 22, 10969. [Google Scholar] [CrossRef]
- Tate, J.G.; Bamford, S.; Jubb, H.C.; Sondka, Z.; Beare, D.M.; Bindal, N.; Boutselakis, H.; Cole, C.G.; Creatore, C.; Dawson, E.; et al. COSMIC: The Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2019, 47, D941–D947. [Google Scholar] [CrossRef] [Green Version]
- Nusinow, D.P.; Szpyt, J.; Ghandi, M.; Rose, C.M.; McDonald, E.R., 3rd; Kalocsay, M.; Jané-Valbuena, J.; Gelfand, E.; Schweppe, D.K.; Jedrychowski, M.; et al. Quantitative Proteomics of the Cancer Cell Line Encyclopedia. Cell 2020, 180, 387–402.e16. [Google Scholar] [CrossRef]
- Musa, A.; Tripathi, S.; Dehmer, M.; Emmert-Streib, F. L1000 Viewer: A Search Engine and Web Interface for the LINCS Data Repository. Front. Genet. 2019, 10, 557. [Google Scholar] [CrossRef]
- Iwata, M.; Sawada, R.; Iwata, H.; Kotera, M.; Yamanishi, Y. Elucidating the modes of action for bioactive compounds in a cell-specific manner by large-scale chemically-induced transcriptomics. Sci. Rep. 2017, 7, 40164. [Google Scholar] [CrossRef]
- OECD Guidance Document on the In Vitro Bhas 42 Cell Transformation Assay (BHAS 42 CTA); OECD Publishing: Paris, France, 2016.
- OECD Guidance Document on the In Vitro Syrian Hamster Embryo (She) Cell Transformation Assay; Series on Testing & Assessement No. 214; JTOECD Publishing: Paris, France, 2015.
- Ramaiahgari, S.C.; Auerbach, S.S.; Saddler, T.; Rice, J.R.; E Dunlap, P.; Sipes, N.S.; DeVito, M.J.; Shah, R.R.; Bushel, P.R.; A Merrick, B.; et al. The Power of Resolution: Contextualized Understanding of Biological Responses to Liver Injury Chemicals Using High-throughput Transcriptomics and Benchmark Concentration Modeling. Toxicol. Sci. 2019, 169, 553–566. [Google Scholar] [CrossRef]
- ter Braak, B.; Niemeijer, M.; Boon, R.; Parmentier, C.; Baze, A.; Richert, L.; Huppelschoten, S.; Wink, S.; Verfaillie, C.; van de Water, B. Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes. Toxicol. Vitr. 2021, 73, 105107. [Google Scholar] [CrossRef]
- OECD Guidance Document on Good In Vitro Method Practices (GIVIMP); OECD Publishing: Paris, France, 2018; Volume 1.
- Jacobs, M.; Janssens, W.; Bernauer, U.; Brandon, E.; Coecke, S.; Combes, R.; Edwards, P.; Freidig, A.; Freyberger, A.; Kolanczyk, R.; et al. The Use of Metabolising Systems for In Vitro Testing of Endocrine Disruptors. Curr. Drug Metab. 2008, 9, 796–826. [Google Scholar] [CrossRef] [Green Version]
- Jacobs, M.N.; Laws, S.C.; Willett, K.; Schmieder, P.; Odum, J.; Bovee, T.F. In vitro metabolism and bioavailability tests for endocrine active substances: What is needed next for regulatory purposes? ALTEX 2013, 30, 331–351. [Google Scholar] [CrossRef] [Green Version]
- Iorio, F.; Knijnenburg, T.A.; Vis, D.J.; Bignell, G.R.; Menden, M.P.; Schubert, M.; Aben, N.; Gonçalves, E.; Barthorpe, S.; Lightfoot, H.; et al. A Landscape of Pharmacogenomic Interactions in Cancer. Cell 2016, 166, 740–754. [Google Scholar] [CrossRef] [Green Version]
- Barretina, J.; Caponigro, G.; Stransky, N.; Venkatesan, K.; Margolin, A.A.; Kim, S.; Wilson, C.J.; Lehár, J.; Kryukov, G.V.; Sonkin, D.; et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 2012, 483, 603–607. [Google Scholar] [CrossRef] [Green Version]
- Jiang, G.; Zhang, S.; Yazdanparast, A.; Li, M.; Pawar, A.V.; Liu, Y.; Inavolu, S.M.; Cheng, L. Comprehensive comparison of molecular portraits between cell lines and tumors in breast cancer. BMC Genom. 2016, 17, 281–301. [Google Scholar] [CrossRef] [Green Version]
- Vincent, K.M.; Findlay, S.D.; Postovit, L.M. Assessing breast cancer cell lines as tumour models by comparison of mRNA expression profiles. Breast Cancer Res. 2015, 17, 114. [Google Scholar] [CrossRef] [Green Version]
- Pickles, J.C.; Pant, K.; Mcginty, L.A.; Yasaei, H.; Roberts, T.; Scott, A.D.; Newbold, R.F. A mechanistic evaluation of the Syrian hamster embryo cell transformation assay (pH 6.7) and molecular events leading to senescence bypass in SHE cells. Mutat. Res. Toxicol. Environ. Mutagen. 2016, 802, 50–58. [Google Scholar] [CrossRef]
- Buchmueller, J.; Sprenger, H.; Ebmeyer, J.; Rasinger, J.D.; Creutzenberg, O.; Schaudien, D.; Hengstler, J.G.; Guenther, G.; Braeuning, A.; Hessel-Pras, S. Pyrrolizidine alkaloid-induced transcriptomic changes in rat lungs in a 28-day subacute feeding study. Arch. Toxicol. 2021, 95, 2785–2796. [Google Scholar] [CrossRef]
- Nicolaidou, V.; Koufaris, C. Application of Transcriptomic and MicroRNA Profiling in the Evaluation of Potential Liver Car-cinogens. Toxicol. Ind. Health 2020, 36. [Google Scholar]
- Fernandes, J.; Chandler, J.D.; Lili, L.N.; Uppal, K.; Hu, X.; Hao, L.; Go, Y.-M.; Jones, D.P. Transcriptome Analysis Reveals Distinct Responses to Physiologic versus Toxic Manganese Exposure in Human Neuroblastoma Cells. Front. Genet. 2019, 10, 676. [Google Scholar] [CrossRef] [Green Version]
- Jiang, J.; Pieterman, C.D.; Ertaylan, G.; Peeters, R.L.M.; de Kok, T.M.C.M. The application of omics-based human liver platforms for investigating the mechanism of drug-induced hepatotoxicity in vitro. Arch. Toxicol. 2019, 93, 3067–3098. [Google Scholar] [CrossRef] [Green Version]
- Klaren, W.D.; Ring, C.; A Harris, M.; Thompson, C.M.; Borghoff, S.; Sipes, N.S.; Hsieh, J.-H.; Auerbach, S.S.; E Rager, J. Identifying Attributes That Influence In Vitro-to-In Vivo Concordance by Comparing In Vitro Tox21 Bioactivity Versus In Vivo DrugMatrix Transcriptomic Responses Across 130 Chemicals. Toxicol. Sci. 2018, 167, 157–171. [Google Scholar] [CrossRef] [Green Version]
- Janesick, A.S.; Dimastrogiovanni, G.; Vanek, L.; Boulos, C.; Chamorro-García, R.; Tang, W.; Blumberg, B. On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens. Environ. Health Perspect. 2016, 124, 1214–1226. [Google Scholar] [CrossRef] [Green Version]
- Buckalew, A.R.; Wang, J.; Murr, A.S.; Deisenroth, C.; Stewart, W.M.; Stoker, T.E.; Laws, S.C. Evaluation of potential sodium-iodide symporter (NIS) inhibitors using a secondary Fischer rat thyroid follicular cell (FRTL-5) radioactive iodide uptake (RAIU) assay. Arch. Toxicol. 2020, 94, 873–885. [Google Scholar] [CrossRef]
- Wetterstrand, K.A. DNA Sequencing Costs: Data from the NHGRI Genome Sequencing Program (GSP). Available online: Www.Genome.Gov/Sequencingcostsdata (accessed on 19 May 2022).
- Alexander-Dann, B.; Pruteanu, L.L.; Oerton, E.; Sharma, N.; Berindan-Neagoe, I.; Módos, D.; Bender, A. Developments in toxicogenomics: Understanding and predicting compound-induced toxicity from gene expression data. Mol. Omics 2018, 14, 218–236. [Google Scholar] [CrossRef] [Green Version]
- Edgar, R.; Domrachev, M.; Lash, A.E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002, 30, 207–210. [Google Scholar] [CrossRef] [Green Version]
- Athar, A.; Füllgrabe, A.; George, N.; Iqbal, H.; Huerta, L.; Ali, A.; Snow, C.; Fonseca, N.; Petryszak, R.; Papatheodorou, I.; et al. ArrayExpress update–from bulk to single-cell expression data. Nucleic Acids Res. 2018, 47, D711–D715. [Google Scholar] [CrossRef] [PubMed]
- OECD Guidance Document on the Validation and International Acceptance of New or Updated Test Methods for Hazard Assessment. Series on Testing and Assessment 2005, No. 34; OECD Publishing: Paris, France.
- Kastan, N.; Gnedeva, K.; Alisch, T.; Petelski, A.; Huggins, D.J.; Chiaravalli, J.; Aharanov, A.; Shakked, A.; Tzahor, E.; Nagiel, A.; et al. Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues. Nat. Commun. 2021, 12, 3100. [Google Scholar] [CrossRef] [PubMed]
- Doudican, N.A.; Orlow, S.J. Inhibition of the CRAF/prohibitin interaction reverses CRAF-dependent resistance to vemurafenib. Oncogene 2016, 36, 423–428. [Google Scholar] [CrossRef]
- Davis, A.P.; Grondin, C.J.; Johnson, R.J.; Sciaky, D.; Wiegers, J.; Wiegers, T.C.; Mattingly, C.J. Comparative Toxicogenomics Database (CTD): Update 2021. Nucleic Acids Res. 2021, 49, D1138–D1143. [Google Scholar] [CrossRef] [PubMed]
- Igarashi, Y.; Nakatsu, N.; Yamashita, T.; Ono, A.; Ohno, Y.; Urushidani, T.; Yamada, H. Open TG-GATEs: A large-scale toxicogenomics database. Nucleic Acids Res. 2014, 43, D921–D927. [Google Scholar] [CrossRef] [PubMed]
- Lamb, J.; Crawford, E.D.; Peck, D.; Modell, J.W.; Blat, I.C.; Wrobel, M.J.; Lerner, J.; Brunet, J.-P.; Subramanian, A.; Ross, K.N.; et al. The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease. Science 2006, 313, 1929–1935. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Subramanian, A.; Narayan, R.; Corsello, S.M.; Peck, D.D.; Natoli, T.E.; Lu, X.; Gould, J.; Davis, J.F.; Tubelli, A.A.; Asiedu, J.K.; et al. A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell 2017, 171, 1437–1452.e17. [Google Scholar] [CrossRef] [PubMed]
- Rudel, R.A.; Ackerman, J.M.; Attfield, K.R.; Brody, J.G. New Exposure Biomarkers as Tools for Breast Cancer Epidemiology, Biomonitoring, and Prevention: A Systematic Approach Based on Animal Evidence. Environ. Health Perspect. 2014, 122, 881–895. [Google Scholar] [CrossRef] [Green Version]
- Alvarez, M.J.; Shen, Y.; Giorgi, F.M.; Lachmann, A.; Ding, B.B.; Ye, B.H.; Califano, A. Functional characterization of somatic mutations in cancer using network-based inference of protein activity. Nat. Genet. 2016, 48, 838–847. [Google Scholar] [CrossRef]
- Sovadinová, I.; Upham, B.L.; Trosko, J.E.; Babica, P. Applicability of Scrape Loading-Dye Transfer Assay for Non-Genotoxic Carcinogen Testing. Int. J. Mol. Sci. 2021, 22, 8977. [Google Scholar] [CrossRef]
- Batista Leite, S.; Cipriano, M.; Carpi, D.; Coecke, S.; Holloway, M.; Corvi, R.; Worth, A.; Barroso, J.; Whelan, M. Establishing the Scientific Validity of Complex in Vitro Models: Results of a EURL ECVAM Survey; EUR 30556 EN; Publications Office of the European Union: Luxembourg, 2021. [Google Scholar]
- Pfuhler, S.; Pirow, R.; Downs, T.R.; Haase, A.; Hewitt, N.; Luch, A.; Merkel, M.; Petrick, C.; Said, A.; Schäfer-Korting, M.; et al. Validation of the 3D reconstructed human skin Comet assay, an animal-free alternative for following-up positive results from standard in vitro genotoxicity assays. Mutagenesis 2020, 36, 19–35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mišík, M.; Nersesyan, A.; Kment, M.; Ernst, B.; Setayesh, T.; Ferk, F.; Holzmann, K.; Krupitza, G.; Knasmueller, S. Micronucleus assays with the human derived liver cell line (Huh6): A promising approach to reduce the use of laboratory animals in genetic toxicology. Food Chem. Toxicol. 2021, 154, 112355. [Google Scholar] [CrossRef] [PubMed]
- Wills, J.W.; Halkes-Wellstead, E.; Summers, H.D.; Rees, P.; E Johnson, G. Empirical comparison of genotoxic potency estimations: The in vitro DNA-damage ToxTracker endpoints versus the in vivo micronucleus assay. Mutagenesis 2021, 36, 311–320. [Google Scholar] [CrossRef] [PubMed]
- Mi, H.; Muruganujan, A.; Thomas, P.D. PANTHER in 2013: Modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees. Nucleic Acids Res. 2013, 41, D377–D386. [Google Scholar] [CrossRef] [Green Version]
- Thomas, P.D.; Campbell, M.J.; Kejariwal, A.; Mi, H.; Karlak, B.; Daverman, R.; Diemer, K.; Muruganujan, A.; Narechania, A. PANTHER: A library of protein families and subfamilies indexed by function. Genome Res. 2003, 13, 2129–2141. [Google Scholar] [CrossRef]
Quantigene | Attagene cis-Factorial (n = 83) | nCounter Pan Cancer (n = 767) | Trusight Pan Cancer (n = 1388) | BCScreen Method (n = 500) | |||
---|---|---|---|---|---|---|---|
Cancer Pathway (n = 85) | Stress &Toxicity (n = 84) | Epigenetic Chromatin Modification Enzymes (n = 44) | |||||
Biological process: | |||||||
cell adhesion | √ | √ | √ | ||||
angiogenesis | √ | √ | √ | √ | √ | ||
apoptosis | √ | √ | √ | √ | √ | √ | |
cell cycle | √ | √ | √ | √ | √ | √ | √ |
development | √ | √ | √ | √ | |||
differentiation | √ | √ | √ | √ | √ | ||
DNA repair | √ | √ | √ | ||||
epigenetic alteration | √ | √ | √ | √ | |||
genotoxicity | √ | √ | √ | √ | √ | ||
growth | √ | √ | √ | √ | √ | √ | √ |
hormone alteration | √ | √ | √ | √ | √ | √ | |
immortalization | √ | ||||||
immune response | √ | √ | √ | √ | √ | ||
inflammatory response | √ | √ | √ | √ | |||
mammary gland related | √ | √ | √ | ||||
proliferation | √ | √ | √ | √ | √ | ||
oxidative stress response | √ | √ | √ | √ | √ | √ | |
transcriptional misregulation | √ | √ | |||||
tumour invasion | √ | √ | √ | √ | |||
tumour suppression | √ | √ | √ | ||||
xenobiotic metabolism | √ | √ | √ | √ |
Gene Sets | Descriptions of Gene Sets | Covering Biological Processes | Pathways | Cells/Tissue Used & References |
---|---|---|---|---|
HALLMARK_ XENOBIOTIC_ METABOLISM | Genes encoding proteins involved in processing of drugs and other xenobiotics. | P450 induction | xenobiotic metabolism | Liver cancer [53,54] |
HALLMARK_ ANDROGEN_ RESPONSE | Genes defining response to androgens. | P450 induction, receptor binding, transactivation, human receptor | androgen | Prostate cancer [55] |
HALLMARK_ OESTROGEN_ RESPONSE_EARLY | Genes defining early response to oestrogen. | P450 induction, receptor binding, transactivation, human receptor | oestrogen | Prostate cancer [56] |
HALLMARK_ OESTROGEN_RESPONSE_LATE | Genes defining late response to oestrogen. | P450 induction, receptor binding, transactivation, human receptor | oestrogen | Prostate cancer [56] |
RELA_DN.V1_DN RELA_DN.V1_UP | Genes down/up-regulated in HEK293 cells (kidney fibroblasts) upon knockdown of RELA gene by RNAi. | Immunoevasion, immunotoxicity, inflammation | NFκB | Breast cancer [57] Hepatocellular carcinoma [58] |
HALLMARK_IL6_ JAK_STAT3_ SIGNALING | Genes up-regulated by IL6 via STAT3, e.g., during acute phase response. | Immunoevasion, immunotoxicity, inflammation | IL-6 | Osteosarcoma [59] |
HALLMARK_ INFLAMMATORY_ RESPONSE | Genes defining inflammatory response. | Immunoevasion, immunotoxicity, inflammation | inflammation | Osteosarcoma [59] |
HALLMARK_ INTERFERON_ ALPHA_RESPONSE | Genes up-regulated in response to alpha interferon proteins. | Immunoevasion, immunotoxicity | Interferon α | Osteosarcoma [59] |
HALLMARK_ INTERFERON_ GAMMA_RESPONSE | Genes up-regulated in response to IFNG. | Immunoevasion, immunotoxicity | interferon γ | Osteosarcoma [59] |
IL15_UP.V1_DN IL15_UP.V1_UP | Genes down/up-regulated in Sez-4 cells (T lymphocyte) that were first starved of IL2 and then stimulated with IL15. | Immunoevasion, immunotoxicity | IL15 | Breast cancer [60] Oesophageal carcinoma [61] |
IL21_UP.V1_DN IL21_UP.V1_UP | Genes down/up-regulated in Sez-4 cells (T lymphocyte) that were first starved of IL2 and then stimulated with IL21. | Immunoevasion, immunotoxicity | IL21 | U-2932 diffuse large B cell lymphoma cell line [62] |
IL2_UP.V1_DN IL2_UP.V1_UP | Genes down/up-regulated in Sez-4 cells (T lymphocyte) that were first starved of IL2 and then stimulated with IL2. | Immunoevasion, immunotoxicity | IL2 | U-2932 diffuse large B cell lymphoma cell line [62] |
JAK2_DN.V1_DN JAK2_DN.V1_UP | Genes down/up-regulated in HEL cells (erythroleukaemia) after knockdown of JAK2 gene by RNAi. | Immunoevasion, immunotoxicity, inflammation | JAK-STAT | U-2932 diffuse large B cell lymphoma cell line [62] |
HALLMARK_ REACTIVE_ OXYGEN_ SPECIES_PATHWAY | Genes up-regulated by reactive oxygen species (ROS). | Oxidative stress | oxidative stress response | HT1080 human fibrosarcoma [63] |
NFE2L2.V2 | Genes down-regulated in MEF cells (embryonic fibroblasts) after knockout of NFE2L2 gene. | Oxidative stress, senescence | NRF2-KEAP1 | A549 Lung cancer cell line [64] |
HALLMARK_ HYPOXIA | Genes up-regulated in response to low oxygen levels (hypoxia). | Angiogenesis | hypoxia response | Glioblastoma [65] |
EGFR_UP.V1_DN EGFR_UP.V1_UP | Genes down/up-regulated in MCF7 cells (breast cancer) positive for ESR1 and engineered to express ligand-activatable EGFR. | Cell proliferation, cell transformation | RTK-RAS-RAF | Pulmonary arcinoids [66] Ameloblastoma [67] |
ERBB2_UP.V1_DN ERBB2_UP.V1_UP | Genes down/up-regulated in MCF7 cells (breast cancer) positive for ESR1 and engineered to express ligand-activatable ERBB2. | Cell proliferation, cell transformation | RTK-RAS-RAF | Gastric cancer [68] Huh7 Hepatocellular carcinoma cell line [69] |
KRAS.600_UP.V1_DN KRAS.600_UP.V1_UP | Genes down/up-regulated in four lineages of epithelial cell lines over-expressing an oncogenic form of KRAS gene. | Cell proliferation, cell transformation | RTK-RAS-RAF | Colorectal cancer [70] Ameloblastoma [67] |
RAF_UP.V1_DN RAF_UP.V1_UP | Genes down/up-regulated in MCF7 cells (breast cancer) positive for ESR1 MCF7 cells (breast cancer) stably over-expressing constitutively active RAF1 gene. | Cell proliferation, cell transformation | RTK-RAS-RAF | Neuroblastoma [71] |
MEK_UP.V1_DN MEK_UP.V1_UP | Genes down/up-regulated in MCF7 cells (breast cancer) positive for ESR1 MCF7 cells (breast cancer) stably over-expressing constitutively active gene. | Cell proliferation, cell transformation | RTK-RAS-RAF | Neuroblastoma [71] T cell leukemia cell linnes [72] |
AKT_UP.V1_DN AKT_UP.V1_UP | Genes down/up-regulated in mouse prostate by transgenic expression of human AKT1 gene vs controls. | Cell proliferation, cell transformation | PI3K-AKT-mTOR | Bladder cancer [73] Hepatocellular carcinoma [58] |
PTEN_DN.V1_DN PTEN_DN.V1_UP | Genes down/up-regulated upon knockdown of PTEN by RNAi. | Cell proliferation, cell transformation | PI3K-AKT-mTOR | Small cell lung cancer [74] |
MTOR_UP.V1_DN MTOR_UP.V1_UP | Genes down/up-regulated by everolimus in prostate tissue. | Cell proliferation, cell transformation | PI3K-AKT-mTOR | Keratinocytes/ fibroblast [75] T cell leukaemia cell lines [72] |
MYC_UP.V1_DN MYC_UP.V1_UP | Genes down/up-regulated in primary epithelial breast cancer cell culture over-expressing MYC gene. | Cell proliferation, cell transformation | MYC | Hepatocellular carcinoma [58] Colorectal cancer [76] |
YAP1_DN YAP1_UP | Genes down/up-regulated in MCF10A cells (breast cancer) over-expressing YAP1 gene. | Cell proliferation, cell transformation | Hippo | Hepatocellular carcinoma [58] Prostate cancer [77] |
WNT_UP.V1_DN WNT_UP.V1_UP | Genes down/up-regulated in C57MG cells (mammary epithelium) by over-expression of WNT1 gene. | Cell proliferation, cell transformation | WNT-β-catenin | Peripheral nerve sheath tumour [78] Hepatocellular carcinoma [58] |
BCAT.100_UP.V1_DN BCAT.100_UP.V1_UP | Genes down/up-regulated in HEK293 cells (kidney fibroblasts) expressing constitutively active form of CTNNB1 gene. | Cell proliferation, cell transformation | WNT-β-catenin | Hepatocellular carcinoma [58] Acute lympho- blastic leukaemia [79] |
LEF1_UP.V1_DN LEF1_UP.V1_UP | Genes down/up-regulated in DLD1 cells (colon carcinoma) over-expressing LEF1. | Cell proliferation, cell transformation | WNT-β-catenin | Bladder cancer [73] Hepatocellular carcinoma [58] |
TGFB_UP.V1_DN TGFB_UP.V1_UP | Genes down/up-regulated in a panel of epithelial cell lines by TGFB1. | Cell proliferation, cell transformation | TGF-β | T cell leukaemia cell lines [72] Breast cancer cell lines [80] |
NOTCH_DN.V1_DN NOTCH_DN.V1_UP | Genes down/up-regulated in MOLT4 cells (T-ALL) by DAPT, an inhibitor of NOTCH signaling pathway. | Cell proliferation, cell transformation | Notch | Endometrial cancer [81] Oesophageal carcinoma [61] |
E2F1_UP.V1_DN E2F1_UP.V1_UP | Genes down/up-regulated in mouse fibroblasts over-expressing E2F1 gene. | Cell proliferation, cell transformation, senescence | Rb-E2F | Acute myeloid leukaemia [82] Prostate cancer [83] |
RB_DN.V1_DN RB_DN.V1_UP | Genes down/up-regulated in primary keratinocytes from RB1 skin specific knockout mice. | Cell proliferation, cell transformation, senescence | Rb-E2F | Hepatocellular carcinoma [58] Pancreatic cancer [84] |
HALLMARK_ EPITHELIAL_ MESENCHYMAL_ TRANSITION | Genes defining epithelial-mesenchymal transition, as in wound healing, fibrosis and metastasis. | Cell proliferation, loss of gap junction | epithelial-mesenchymal transition | Pan-cancer [85] |
HALLMARK_ UV_RESPONSE_DN HALLMARK_ UV_RESPONSE_UP | Genes down/up-regulated in response to ultraviolet (UV) radiation. | Genetic instability, senescence | UV response | Bone marrow stromal cell [86] Prostate cancer [87] |
ATM_DN.V1_DN ATM_DN.V1_UP | Genes down/up-regulated in HEK293 cells (kidney fibroblasts) upon knockdown of ATM gene by RNAi. | Genetic instability, senescence | ATM-ATR | Hepatocellular carcinoma [58] Endometrial cancer [81] |
BRCA1_DN.V1_DN BRCA1_DN.V1_UP | Genes down/up-regulated in MCF10A cells (breast cancer) upon knockdown of BRCA1 gene by RNAi. | Genetic instability, senescence | BRCA | Hodgkin lymphoma [88] Hepatic stellate cell [89] |
HALLMARK_ DNA_REPAIR | Genes involved in DNA repair. | Genetic instability, senescence | DNA repair | Hepatocellular carcinoma [90] |
HALLMARK_ G2M_CHECKPOINT | Genes involved in the G2/M checkpoint, as in progression through the cell division cycle. | Cell proliferation, cellular transformation, senescence | G2/M checkpoint | Hepatocellular carcinoma [91] |
HALLMARK_ MITOTIC_SPINDLE | Genes important for mitotic spindle assembly. | Cell proliferation, cellular transformation, senescence | mitotic spindle | Breast cancer [92] |
CYCLIN_D1_UP.V1_ DN CYCLIN_D1_UP.V1_ UP | Genes down/up-regulated in MCF7 cells (breast cancer) over-expressing CCND1 gene. | Cell proliferation, cell transformation | Cyclin-CDK | Hepatocellular carcinoma [58] Colorectal cancer [93] |
P53_DN.V1_DN P53_DN.V1_UP | Genes down-regulated in NCI60 panel of cell lines with mutated TP53. | Cell proliferation, cell transformation, genetic instability, senescence, apoptosis | p53 | Colon Adenocarcinoma [94] |
HALLMARK_ APOPTOSIS | Genes mediating programmed cell death (apoptosis) by activation of caspases. | Apoptosis | apoptotic pathways | Colorectal cancer [95] |
HALLMARK_ APICAL_JUNCTION | Genes encoding components of apical junction complex. | Cell proliferation, loss of gap junction | apical junction, epithelial-mesenchymal transition | Colorectal cancer [96] |
VEGF_A_UP.V1_DN VEGF_A_UP.V1_UP | Genes down/up-regulated in HUVEC cells (endothelium) by treatment with VEGFA. | Angiogenesis | angiogenesis | Head and neck squamous cell carcinoma [97] Breast cancer [57] |
HALLMARK_ ANGIOGENESIS | Genes up-regulated during formation of blood vessels (angiogenesis). | Angiogenesis | angiogenesis | Breast cancer [98] |
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Chemicals | Number of Interactions |
---|---|
Estradiol | 46 |
Cyclosporin | 45 |
Benzo[a]pyrene | 40 |
Valproic Acid | 39 |
Calcitriol | 39 |
Tretinoic | 37 |
Coumestrol | 37 |
Tetrachlorodibenzodioxin | 36 |
Copper Sulfate | 35 |
Genistein | 34 |
Cobalt Chloride | 34 |
Resveratrol | 33 |
Acetaminophen | 33 |
7,8-Dihydro-7,8-dihydroxybenzo9apyrene 9,10-oxide | 33 |
Nickel | 32 |
Testosterone | 32 |
Bisphenol A | 32 |
Alfatoxin B1 | 31 |
(+)-JQ1 | 28 |
Sodium arsenite | 26 |
Fluorouracil | 24 |
Cadmium chloride | 22 |
Mustard gas | 22 |
Decitabine | 21 |
Propionaldehyde | 21 |
Dasatinib | 21 |
Tunicamycin | 19 |
Lucanthrone | 19 |
ICG 001 | 19 |
Methotrexate | 19 |
Zoledronic acid | 18 |
Polychlorinated biphenyls | 18 |
Thapsigargin | 17 |
Palbocivlib | 16 |
K 7174 | 16 |
Irinotecan | 15 |
β-methylcholine | 14 |
Cupric acid | 13 |
Vinblastine | 10 |
Chemicals | Number of Interactions |
---|---|
Valproic acid | 77 |
Cyclosporine | 72 |
Estradiol | 62 |
Benzo[a]pyrene | 61 |
7,8-Dihydro-7,8-dihydroxybenzo[a]pyrene 9,10-oxide | 59 |
Tretinoin | 56 |
Copper sulfate | 56 |
Calcitriol | 55 |
Aflatoxin B1 | 53 |
Acetaminophen | 53 |
Nickel | 51 |
Testosterone | 50 |
Coumestrol | 50 |
(+)-JQ1 | 48 |
Troglitazone | 46 |
Tetrachlorodibenzodioxin | 45 |
Cobalt chloride | 43 |
Trichostatin A | 39 |
Arsenic trioxide | 39 |
Quercetin | 38 |
Resveratrol | 37 |
Bisphenol A | 37 |
Genistein | 36 |
Hydrogen peroxide | 35 |
Silicon dioxide | 33 |
Formaldehyde | 33 |
Cisplatin | 33 |
ICG 001 | 30 |
Fluorouracil | 30 |
Methyl methanesulfonate | 28 |
K 7174 | 28 |
Dasatinib | 27 |
Potassium chromate (VI) | 27 |
Phenylmercuric acetate | 27 |
Mustard gas | 27 |
Cadmium | 27 |
Vitamine K3 | 26 |
Tert-butylhydroperoxide | 26 |
Propionaldehyde | 26 |
Methotrexate | 26 |
Doxorubicine | 26 |
Zoledronic acid | 25 |
Thapsigargin | 25 |
Decitabine | 25 |
Cadmium chloride | 25 |
Sodium arsenite | 24 |
Carbamazepine | 24 |
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Oku, Y.; Madia, F.; Lau, P.; Paparella, M.; McGovern, T.; Luijten, M.; Jacobs, M.N. Analyses of Transcriptomics Cell Signalling for Pre-Screening Applications in the Integrated Approach for Testing and Assessment of Non-Genotoxic Carcinogens. Int. J. Mol. Sci. 2022, 23, 12718. https://doi.org/10.3390/ijms232112718
Oku Y, Madia F, Lau P, Paparella M, McGovern T, Luijten M, Jacobs MN. Analyses of Transcriptomics Cell Signalling for Pre-Screening Applications in the Integrated Approach for Testing and Assessment of Non-Genotoxic Carcinogens. International Journal of Molecular Sciences. 2022; 23(21):12718. https://doi.org/10.3390/ijms232112718
Chicago/Turabian StyleOku, Yusuke, Federica Madia, Pierre Lau, Martin Paparella, Timothy McGovern, Mirjam Luijten, and Miriam N. Jacobs. 2022. "Analyses of Transcriptomics Cell Signalling for Pre-Screening Applications in the Integrated Approach for Testing and Assessment of Non-Genotoxic Carcinogens" International Journal of Molecular Sciences 23, no. 21: 12718. https://doi.org/10.3390/ijms232112718