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Unraveling the potential of senescence-related genes in guiding clinical therapy of lung adenocarcinoma patients

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Abstract

Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer. In recent years, cell senescence emerges as a potential therapeutic target of cancer therapy. However, the role of cell senescence in LUAD has not been comprehensively unveiled. One single cell RNA sequencing (scRNA-seq) dataset (GSE149655) and two bulk RNA-seq datasets (TCGA and GSE31210) of LUAD were included. Seurat R package was used to process scRNA-seq data and identify immune cell subgroups. Single sample gene set enrichment analysis (ssGSEA) was performed to calculate enrichment score of senescence-related pathways. Senescence-based molecular subtyping for LUAD samples was conducted through unsupervised consensus clustering. pRRophetic package was introduced to analysis drug sensitivity. The senescence-associated risk model was established using univariate regression and stepAIC methods. Western blot, RT-qPCR, immunofluorescence assay and CCK-8 were used to explore the effect of CYCS in LUAD cell lines. Malignant immune cells had remarkedly higher enrichment of senescence-related pathways than non-malignant cells. P53 signaling and DNA damage telomere stress induced senescence pathways were found to be significantly activated in LUAD samples compared with normal samples. We identified two clusters (clust1 and clust2) based on senescence-related genes. Clust1 had severe genomic instability, aggravated senescent features, and low immune and stromal infiltration. The senescence-associated risk model including CASP9, CHEK1, CYCS, SERPINE1, SESN2, TP53I3, LMNB1, RAD50 and TERF2IP, was effective to distinguish high- and low-risk groups. Moreover, low-risk group exhibited sensitive responses to immunotherapy and chemotherapeutic drugs. In vitro experiments results showed that CYCS expression was increased and promoted cell viability in LUAD cell lines. This study explored the important role of senescence in LUAD progression, and confirmed the potential of senescence-related genes in predicting LUAD prognosis and response to immunotherapy and chemotherapy.

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References

  • Alique M, Sánchez-López E, Bodega G, Giannarelli C, Carracedo J, Ramírez R (2020) Hypoxia-inducible factor-1α: the master regulator of endothelial cell senescence in vascular aging. Cells 9(1)

  • Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J et al (2017) Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet (london, England) 389(10064):67–76

    CAS  PubMed  Google Scholar 

  • Battram AM, Bachiller M, Martín-Antonio B (2020) Senescence in the development and response to cancer with immunotherapy: a double-edged sword. Int J Mol Sci 21(12)

  • Behmoaras J, Gil J (2021) Similarities and interplay between senescent cells and macrophages. J Cell Biol 220(2)

  • Blanche P, Dartigues JF, Jacqmin-Gadda H (2013) Estimating and comparing time-dependent areas under receiver operating characteristic curves for censored event times with competing risks. Stat Med 32(30):5381–5397

    PubMed  Google Scholar 

  • Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639

    CAS  PubMed  PubMed Central  Google Scholar 

  • Buechler MB, Fu W, Turley SJ (2021) Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer. Immunity 54(5):903–915

    CAS  PubMed  Google Scholar 

  • Campbell JD, Alexandrov A, Kim J, Wala J, Berger AH, Pedamallu CS et al (2016) Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet 48(6):607–616

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA (2018) Profiling tumor infiltrating immune cells with CIBERSORT. Methods Mol Biol (clifton NJ) 1711:243–259

    CAS  Google Scholar 

  • Chen KY, Chen CC, Chang YC, Chang MC (2019) Resveratrol induced premature senescence and inhibited epithelial-mesenchymal transition of cancer cells via induction of tumor suppressor Rad9. PLoS One 14(7):e0219317

    CAS  PubMed  PubMed Central  Google Scholar 

  • Clough E, Barrett T (2016) The Gene Expression Omnibus Database. Methods Mol Biol (clifton NJ) 1418:93–110

    Google Scholar 

  • (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511(7511):543-50

  • Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J et al (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6(12):2853–2868

    PubMed  Google Scholar 

  • Cortesi M, Zanoni M, Pirini F, Tumedei MM, Ravaioli S, Rapposelli IG, et al (2021) Pancreatic cancer and cellular senescence: tumor microenvironment under the spotlight. Int J Mol Sci 23(1)

  • Cuzick J, Swanson GP, Fisher G, Brothman AR, Berney DM, Reid JE et al (2011) Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol 12(3):245–255

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dang HH, Ta HDK, Nguyen TTT, Anuraga G, Wang CY, Lee KH et al (2022) Prospective role and immunotherapeutic targets of sideroflexin protein family in lung adenocarcinoma: evidence from bioinformatics validation. Funct Integr Genomics 22(5):1057–1072

    CAS  PubMed  Google Scholar 

  • De Jaeghere EA, Denys HG, De Wever O (2019) Fibroblasts fuel immune escape in the tumor microenvironment. Trends Cancer 5(11):704–723

    PubMed  Google Scholar 

  • Gao R, Bai S, Henderson YC, Lin Y, Schalck A, Yan Y et al (2021) Delineating copy number and clonal substructure in human tumors from single-cell transcriptomes. Nat Biotechnol 39(5):599–608

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C et al (2019) Cellular senescence: defining a path forward. Cell 179(4):813–827

    CAS  PubMed  Google Scholar 

  • Gribov A, Sill M, Lück S, Rücker F, Döhner K, Bullinger L et al (2010) SEURAT: visual analytics for the integrated analysis of microarray data. BMC Med Genomics 3:21

    PubMed  PubMed Central  Google Scholar 

  • Hänzelmann S, Castelo R, Guinney J (2013) GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14:7

    PubMed  PubMed Central  Google Scholar 

  • Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X et al (2018) Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med 24(10):1550–1558

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K (2017) KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 45(D1):D353–D361

    CAS  PubMed  Google Scholar 

  • Kelly J, Ali Khan A, Yin J, Ferguson TA, Apte RS (2007) Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice. J Clin Investig 117(11):3421–3426

    CAS  PubMed  PubMed Central  Google Scholar 

  • Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 98(21):12072–12077

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24(22):2463–2479

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P (2015) The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 1(6):417–425

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu JY, Souroullas GP, Diekman BO, Krishnamurthy J, Hall BM, Sorrentino JA et al (2019) Cells exhibiting strong p16(INK4a) promoter activation in vivo display features of senescence. Proc Natl Acad Sci USA 116(7):2603–2611

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu H, Zhao H, Sun Y (2021) Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. Semin Cancer Biol 86(Pt 3):769–781

    PubMed  Google Scholar 

  • Masiero M, Simões FC, Han HD, Snell C, Peterkin T, Bridges E et al (2013) A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis. Cancer Cell 24(2):229–241

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G (2011) GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol 2(4):R41

    Google Scholar 

  • Mijit M, Caracciolo V, Melillo A, Amicarelli F, Giordano A (2020) Role of p53 in the regulation of cellular senescence. Biomolecules 10(3)

  • Muz B, de la Puente P, Azab F, Azab AK (2015) The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (auckland NZ) 3:83–92

    Google Scholar 

  • Oishi Y, Manabe I (2016) Macrophages in age-related chronic inflammatory diseases. NPJ Aging Mech Dis 2:16018

    PubMed  PubMed Central  Google Scholar 

  • Pérez-Mancera PA, Young AR, Narita M (2014) Inside and out: the activities of senescence in cancer. Nat Rev Cancer 14(8):547–558

    PubMed  Google Scholar 

  • Prasanna PG, Citrin DE, Hildesheim J, Ahmed MM, Venkatachalam S, Riscuta G et al (2021) Therapy-induced senescence: opportunities to improve anticancer therapy. J Natl Cancer Inst 113(10):1285–1298

    PubMed  PubMed Central  Google Scholar 

  • Pribluda A, Elyada E, Wiener Z, Hamza H, Goldstein RE, Biton M et al (2013) A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell 24(2):242–256

    CAS  PubMed  Google Scholar 

  • Ruhland MK, Loza AJ, Capietto AH, Luo X, Knolhoff BL, Flanagan KC et al (2016) Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat Commun 7:11762

    CAS  PubMed  PubMed Central  Google Scholar 

  • Salas-Benito D, Eguren-Santamaria I, Sanmamed MF (2021) Senescent T cells as a resistance mechanism to lung cancer immunotherapy. Clin Cancer Res Off J Am Assoc Cancer Res 27(2):374–376

    CAS  Google Scholar 

  • Shay JW (2016) Role of telomeres and telomerase in aging and cancer. Cancer Discov 6(6):584–593

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shen W, Song Z, Xiao Z, Huang M, Shen D, Gao P et al (2022) Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform. IMeta 1(3):e36

    Google Scholar 

  • Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545–15550

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tirpe AA, Gulei D, Ciortea SM, Crivii C, Berindan-Neagoe I (2019) Hypoxia: overview on hypoxia-mediated mechanisms with a focus on the role of HIF genes. Int J Mol Sci 20(24)

  • Tomczak K, Czerwińska P, Wiznerowicz M (2015) The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (poznan Poland) 19(1a):A68-77

    Google Scholar 

  • Wang L, Lankhorst L, Bernards R (2022) Exploiting senescence for the treatment of cancer. Nat Rev Cancer 22(6):340–355

    CAS  PubMed  Google Scholar 

  • Wilkerson MD, Hayes DN (2010) ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics (oxford England) 26(12):1572–1573

    CAS  PubMed  Google Scholar 

  • Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V et al (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445(7128):656–660

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yasuda T, Baba H, Ishimoto T (2021) Cellular senescence in the tumor microenvironment and context-specific cancer treatment strategies. FEBS J

  • Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W et al (2013) Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 4:2612

    PubMed  Google Scholar 

  • Zhang Z (2016) Variable selection with stepwise and best subset approaches. Ann Transl Med 4(7):136

    PubMed  PubMed Central  Google Scholar 

  • Zhang XP, Liu F, Wang W (2011) Two-phase dynamics of p53 in the DNA damage response. Proc Natl Acad Sci USA 108(22):8990–8995

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Lan Y, Xu J, Quan F, Zhao E, Deng C et al (2019) Cell Marker: a manually curated resource of cell markers in human and mouse. Nucleic Acids Res 47(D1):D721–D728

    CAS  PubMed  Google Scholar 

  • Zhang J, He T, Xue L, Guo H (2021) Senescent T cells: a potential biomarker and target for cancer therapy. EBioMedicine 68:103409

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou R, Zhou J, Muhuitijiang B, Tan W (2022) Construction and experimental validation of a B cell senescence-related gene signature to evaluate prognosis and immunotherapeutic sensitivity in bladder cancer. Funct Integr Genomics 23(1):3

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, No. 59, Haier RoadLaoshan DistrictShandong Province, 266001, Qingdao, China

    Chuan Liu & Xiaojuan Wei

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  1. Chuan Liu
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All authors contributed to this present work. CL concepted and designed the research and acquired the data. XJW analyzed and interpreted data. XJW obtained funding and drafted the manuscript. CL revised manuscript for important intellectual content. All authors read and approved the manuscript.

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Correspondence to Xiaojuan Wei.

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Liu, C., Wei, X. Unraveling the potential of senescence-related genes in guiding clinical therapy of lung adenocarcinoma patients. Funct Integr Genomics 23, 188 (2023). https://doi.org/10.1007/s10142-023-01073-5

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