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Current Cancer Drug Targets

Author(s): Yan Deng, Yan Lin, Bin Zhou, Qian Jing and Wei Zhang*

DOI: 10.2174/1568009623666230414140609

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Identification of Necroptosis-related Subtypes and Characterization of Tumor Microenvironment Infiltration in Non-small Cell Lung Cancer

Page: [80 - 93] Pages: 14

  • * (Excluding Mailing and Handling)

Abstract

Background: Necroptosis is correlated with the development, prognosis, and treatment of tumors. However, the function of necroptosis-associated genes (NRGs) in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC) remains unclear.

Methods: In this study, 1210 NSCLC samples were classified into different subtypes based on the expression of 66 NRGs by unsupervised clustering analysis, and further analyzed the TME characteristics of these subtypes. In addition, we identified common differentially expressed genes (co-DEGs) in NRG subtypes and constructed the NRG score using principal component analysis (PCA) to assess the NRG-mediated TME characteristics of patients with NSCLC.

Results: Using unsupervised cluster analysis, 1210 NSCLC samples were divided into NRGcluster A and B subtypes. The NRGcluster B survived significantly better than the NRGcluster A. TME characterization revealed that NRGcluster B was upregulated in immune and stromal signaling activation, whereas NRGcluster A was upregulated in oncogenic signaling. The NRG score constructed based on co-DEGs of the two NRG-related subtypes was positively correlated with immune cell infiltration and negatively correlated with the number of cancer stem cells (CSCs) and tumor mutational burden (TMB). In addition, survival was significantly worse in the low-NRG-score group compared to the high-NRG-score group. Finally, the assessment of immunotherapeutic efficacy showed that immunotherapeutic response was significantly worse in the low-NRG-score group compared to the high- NRG-score group.

Conclusion: This research reveals that NRGs are associated with the complexity and diversity of TME in NSCLC. Adopting the NRG score to quantitatively assess NRG-mediated TME in individual patients with NSCLC may help in planning clinical treatment strategies.

[1]
Gong, Y.; Fan, Z.; Luo, G.; Yang, C.; Huang, Q.; Fan, K.; Cheng, H.; Jin, K.; Ni, Q.; Yu, X.; Liu, C. The role of necroptosis in cancer biology and therapy. Mol. Cancer, 2019, 18(1), 100.
[http://dx.doi.org/10.1186/s12943-019-1029-8] [PMID: 31122251]
[2]
Seo, J.; Kim, M.W.; Bae, K.H.; Lee, S.C.; Song, J.; Lee, E.W. The roles of ubiquitination in extrinsic cell death pathways and its implications for therapeutics. Biochem. Pharmacol., 2019, 162, 21-40.
[http://dx.doi.org/10.1016/j.bcp.2018.11.012] [PMID: 30452908]
[3]
Hitomi, J.; Christofferson, D.E.; Ng, A.; Yao, J.; Degterev, A.; Xavier, R.J.; Yuan, J. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell, 2008, 135(7), 1311-1323.
[http://dx.doi.org/10.1016/j.cell.2008.10.044] [PMID: 19109899]
[4]
Wu, W.; Liu, P.; Li, J. Necroptosis: An emerging form of programmed cell death. Crit. Rev. Oncol. Hematol., 2012, 82(3), 249-258.
[http://dx.doi.org/10.1016/j.critrevonc.2011.08.004] [PMID: 21962882]
[5]
Vandenabeele, P.; Galluzzi, L.; Vanden Berghe, T.; Kroemer, G. Molecular mechanisms of necroptosis: An ordered cellular explosion. Nat. Rev. Mol. Cell Biol., 2010, 11(10), 700-714.
[http://dx.doi.org/10.1038/nrm2970] [PMID: 20823910]
[6]
Fritsch, M.; Günther, S.D.; Schwarzer, R.; Albert, M.C.; Schorn, F.; Werthenbach, J.P.; Schiffmann, L.M.; Stair, N.; Stocks, H.; Seeger, J.M.; Lamkanfi, M.; Krönke, M.; Pasparakis, M.; Kashkar, H. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature, 2019, 575(7784), 683-687.
[http://dx.doi.org/10.1038/s41586-019-1770-6] [PMID: 31748744]
[7]
Khoury, M.K.; Gupta, K.; Franco, S.R.; Liu, B. Necroptosis in the pathophysiology of disease. Am. J. Pathol., 2020, 190(2), 272-285.
[http://dx.doi.org/10.1016/j.ajpath.2019.10.012] [PMID: 31783008]
[8]
Yuan, J.; Amin, P.; Ofengeim, D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat. Rev. Neurosci., 2019, 20(1), 19-33.
[http://dx.doi.org/10.1038/s41583-018-0093-1] [PMID: 30467385]
[9]
Lu, Z.; Van Eeckhoutte, H.P.; Liu, G.; Nair, P.M.; Jones, B.; Gillis, C.M.; Nalkurthi, B.C.; Verhamme, F.; Buyle-Huybrecht, T.; Vandenabeele, P.; Vanden Berghe, T.; Brusselle, G.G.; Horvat, J.C.; Murphy, J.M.; Wark, P.A.; Bracke, K.R.; Fricker, M.; Hansbro, P.M. Necroptosis signaling promotes inflammation, airway remodeling, and emphysema in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med., 2021, 204(6), 667-681.
[http://dx.doi.org/10.1164/rccm.202009-3442OC] [PMID: 34133911]
[10]
Feng, X.; Song, Q.; Yu, A.; Tang, H.; Peng, Z.; Wang, X. Receptor-interacting protein kinase 3 is a predictor of survival and plays a tumor suppressive role in colorectal cancer. Neoplasma, 2015, 62(4), 592-601.
[http://dx.doi.org/10.4149/neo_2015_071] [PMID: 25997957]
[11]
Koo, G.B.; Morgan, M.J.; Lee, D.G.; Kim, W.J.; Yoon, J.H.; Koo, J.S.; Kim, S.I.; Kim, S.J.; Son, M.K.; Hong, S.S.; Levy, J.M.M.; Pollyea, D.A.; Jordan, C.T.; Yan, P.; Frankhouser, D.; Nicolet, D.; Maharry, K.; Marcucci, G.; Choi, K.S.; Cho, H.; Thorburn, A.; Kim, Y.S. Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res., 2015, 25(6), 707-725.
[http://dx.doi.org/10.1038/cr.2015.56] [PMID: 25952668]
[12]
Liu, Z.Y.; Zheng, M.; Li, Y.M.; Fan, X.Y.; Wang, J.C.; Li, Z.C.; Yang, H.J.; Yu, J.M.; Cui, J.; Jiang, J.L.; Tang, J.; Chen, Z.N. RIP3 promotes colitis-associated colorectal cancer by controlling tumor cell proliferation and CXCL1-induced immune suppression. Theranostics, 2019, 9(12), 3659-3673.
[http://dx.doi.org/10.7150/thno.32126] [PMID: 31281505]
[13]
McCormick, K.D.; Ghosh, A.; Trivedi, S.; Wang, L.; Coyne, C.B.; Ferris, R.L.; Sarkar, S.N. Innate immune signaling through differential RIPK1 expression promote tumor progression in head and neck squamous cell carcinoma. Carcinogenesis, 2016, 37(5), 522-529.
[http://dx.doi.org/10.1093/carcin/bgw032] [PMID: 26992898]
[14]
Wang, Q.; Chen, W.; Xu, X.; Li, B.; He, W.; Padilla, M.T.; Jang, J.H.; Nyunoya, T.; Amin, S.; Wang, X.; Lin, Y. RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase-mediated suppression of excessive reactive oxygen species. Carcinogenesis, 2013, 34(9), 2119-2128.
[http://dx.doi.org/10.1093/carcin/bgt143] [PMID: 23633517]
[15]
Park, S.; Hatanpaa, K.J.; Xie, Y.; Mickey, B.E.; Madden, C.J.; Raisanen, J.M.; Ramnarain, D.B.; Xiao, G.; Saha, D.; Boothman, D.A.; Zhao, D.; Bachoo, R.M.; Pieper, R.O.; Habib, A.A. The receptor interacting protein 1 inhibits p53 induction through NF-kappaB activation and confers a worse prognosis in glioblastoma. Cancer Res., 2009, 69(7), 2809-2816.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-4079] [PMID: 19339267]
[16]
Newton, K.; Sun, X.; Dixit, V.M. Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol. Cell. Biol., 2004, 24(4), 1464-1469.
[http://dx.doi.org/10.1128/MCB.24.4.1464-1469.2004] [PMID: 14749364]
[17]
Kang, Y.J.; Bang, B.R.; Han, K.H.; Hong, L.; Shim, E.J.; Ma, J.; Lerner, R.A.; Otsuka, M. Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling. Nat. Commun., 2015, 6(1), 8371.
[http://dx.doi.org/10.1038/ncomms9371] [PMID: 26381214]
[18]
Lu, J.V.; Chen, H.C.; Walsh, C.M. Necroptotic signaling in adaptive and innate immunity. Semin. Cell Dev. Biol., 2014, 35, 33-39.
[http://dx.doi.org/10.1016/j.semcdb.2014.07.003] [PMID: 25042848]
[19]
Kaczmarek, A.; Vandenabeele, P.; Krysko, D.V. Necroptosis: The release of damage-associated molecular patterns and its physiological relevance. Immunity, 2013, 38(2), 209-223.
[http://dx.doi.org/10.1016/j.immuni.2013.02.003] [PMID: 23438821]
[20]
Pasparakis, M.; Vandenabeele, P. Necroptosis and its role in inflammation. Nature, 2015, 517(7534), 311-320.
[http://dx.doi.org/10.1038/nature14191] [PMID: 25592536]
[21]
Seifert, L.; Werba, G.; Tiwari, S.; Giao Ly, N.N.; Alothman, S.; Alqunaibit, D.; Avanzi, A.; Barilla, R.; Daley, D.; Greco, S.H.; Torres-Hernandez, A.; Pergamo, M.; Ochi, A.; Zambirinis, C.P.; Pansari, M.; Rendon, M.; Tippens, D.; Hundeyin, M.; Mani, V.R.; Hajdu, C.; Engle, D.; Miller, G. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature, 2016, 532(7598), 245-249.
[http://dx.doi.org/10.1038/nature17403] [PMID: 27049944]
[22]
Iwai, Y.; Ishida, M.; Tanaka, Y.; Okazaki, T.; Honjo, T.; Minato, N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci., 2002, 99(19), 12293-12297.
[http://dx.doi.org/10.1073/pnas.192461099] [PMID: 12218188]
[23]
Wei, Y.; Chen, X.; Ren, X.; Wang, B.; Zhang, Q.; Bu, H.; Qian, J.; Shao, P. Identification of MX2 as a novel prognostic biomarker for sunitinib resistance in clear cell renal cell carcinoma. Front. Genet., 2021, 12, 680369.
[http://dx.doi.org/10.3389/fgene.2021.680369] [PMID: 34306023]
[24]
Ren, X.; Zhang, T.; Chen, X.; Wei, X.; Tian, Y.; Li, G.; Zhang, X.; Zhang, W.; You, Z.; Wang, S.; Qin, C. Early-life exposure to bisphenol A and reproductive-related outcomes in rodent models: A systematic review and meta-analysis. Aging, 2020, 12(18), 18099-18126.
[http://dx.doi.org/10.18632/aging.103620] [PMID: 32996894]
[25]
Zhang, X.; Zhang, T.; Ren, X.; Chen, X.; Wang, S.; Qin, C. Pyrethroids toxicity to male reproductive system and offspring as a function of oxidative stress induction: Rodent studies. Front. Endocrinol., 2021, 12, 656106.
[http://dx.doi.org/10.3389/fendo.2021.656106] [PMID: 34122335]
[26]
Botling, J.; Edlund, K.; Lohr, M.; Hellwig, B.; Holmberg, L.; Lambe, M.; Berglund, A.; Ekman, S.; Bergqvist, M.; Pontén, F.; König, A.; Fernandes, O.; Karlsson, M.; Helenius, G.; Karlsson, C.; Rahnenführer, J.; Hengstler, J.G.; Micke, P. Biomarker discovery in non-small cell lung cancer: Integrating gene expression profiling, meta-analysis, and tissue microarray validation. Clin. Cancer Res., 2013, 19(1), 194-204.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-1139] [PMID: 23032747]
[27]
Dai, W.; Li, Y.; Mo, S.; Feng, Y.; Zhang, L.; Xu, Y.; Li, Q.; Cai, G. A robust gene signature for the prediction of early relapse in stage I-III colon cancer. Mol. Oncol., 2018, 12(4), 463-475.
[http://dx.doi.org/10.1002/1878-0261.12175] [PMID: 29377588]
[28]
Zhang, Y.; Liu, N.; Wang, S. A differential privacy protecting K-means clustering algorithm based on contour coefficients. PLoS One, 2018, 13(11), e0206832.
[http://dx.doi.org/10.1371/journal.pone.0206832] [PMID: 30462662]
[29]
Hänzelmann, S.; Castelo, R.; Guinney, J. GSVA: Gene set variation analysis for microarray and RNA-Seq data. BMC Bioinformatics, 2013, 14(1), 7.
[http://dx.doi.org/10.1186/1471-2105-14-7] [PMID: 23323831]
[30]
Yoshihara, K.; Shahmoradgoli, M.; Martínez, E.; Vegesna, R.; Kim, H.; Torres-Garcia, W.; Treviño, V.; Shen, H.; Laird, P.W.; Levine, D.A.; Carter, S.L.; Getz, G.; Stemke-Hale, K.; Mills, G.B.; Verhaak, R.G.W. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat. Commun., 2013, 4(1), 2612.
[http://dx.doi.org/10.1038/ncomms3612] [PMID: 24113773]
[31]
Charoentong, P.; Finotello, F.; Angelova, M.; Mayer, C.; Efremova, M.; Rieder, D.; Hackl, H.; Trajanoski, Z. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep., 2017, 18(1), 248-262.
[http://dx.doi.org/10.1016/j.celrep.2016.12.019] [PMID: 28052254]
[32]
Zhang, B.; Wu, Q.; Li, B.; Wang, D.; Wang, L.; Zhou, Y.L. m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer. Mol. Cancer, 2020, 19(1), 53.
[http://dx.doi.org/10.1186/s12943-020-01170-0] [PMID: 32164750]
[33]
Iasonos, A.; Schrag, D.; Raj, G.V.; Panageas, K.S. How to build and interpret a nomogram for cancer prognosis. J. Clin. Oncol., 2008, 26(8), 1364-1370.
[http://dx.doi.org/10.1200/JCO.2007.12.9791] [PMID: 18323559]
[34]
Aftab, A.; Shahzad, S.; Hussain, H.M.J.; Khan, R.; Irum, S.; Tabassum, S. CDKN2A/P16INK4A variants association with breast cancer and their in-silico analysis. Breast Cancer, 2019, 26(1), 11-28.
[http://dx.doi.org/10.1007/s12282-018-0894-0] [PMID: 30039340]
[35]
Helgadottir, H.; Olsson, H.; Tucker, M.A.; Yang, X.R.; Höiom, V.; Goldstein, A.M. Phenocopies in melanoma-prone families with germ-line CDKN2A mutations. Genet. Med., 2018, 20(9), 1087-1090.
[http://dx.doi.org/10.1038/gim.2017.216] [PMID: 29215650]
[36]
Overbeek, K.A.; Rodríguez-Girondo, M.D.M.; Wagner, A.; van der Stoep, N.; van den Akker, P.C.; Oosterwijk, J.C.; van Os, T.A.; van der Kolk, L.E.; Vasen, H.F.A.; Hes, F.J.; Cahen, D.L.; Bruno, M.J.; Potjer, T.P. Genotype-phenotype correlations for pancreatic cancer risk in Dutch melanoma families with pathogenic CDKN2A variants. J. Med. Genet., 2021, 58(4), 264-269.
[http://dx.doi.org/10.1136/jmedgenet-2019-106562] [PMID: 32482799]
[37]
Koch, A.; Joosten, S.C.; Feng, Z.; de Ruijter, T.C.; Draht, M.X.; Melotte, V.; Smits, K.M.; Veeck, J.; Herman, J.G.; Van Neste, L.; Van Criekinge, W.; De Meyer, T.; van Engeland, M. Analysis of DNA methylation in cancer: Location revisited. Nat. Rev. Clin. Oncol., 2018, 15(7), 459-466.
[http://dx.doi.org/10.1038/s41571-018-0004-4] [PMID: 29666440]
[38]
Lambert, S.A.; Jolma, A.; Campitelli, L.F.; Das, P.K.; Yin, Y.; Albu, M.; Chen, X.; Taipale, J.; Hughes, T.R.; Weirauch, M.T. The human transcription factors. Cell, 2018, 172(4), 650-665.
[http://dx.doi.org/10.1016/j.cell.2018.01.029] [PMID: 29425488]
[39]
Doroshow, D.B.; Bhalla, S.; Beasley, M.B.; Sholl, L.M.; Kerr, K.M.; Gnjatic, S.; Wistuba, I.I.; Rimm, D.L.; Tsao, M.S.; Hirsch, F.R. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol., 2021, 18(6), 345-362.
[http://dx.doi.org/10.1038/s41571-021-00473-5] [PMID: 33580222]
[40]
Borish, L.C.; Steinke, J.W. 2. Cytokines and chemokines. J. Allergy Clin. Immunol., 2003, 111(S2), S460-S475.
[http://dx.doi.org/10.1067/mai.2003.108] [PMID: 12592293]
[41]
Taniguchi, K.; Karin, M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin. Immunol., 2014, 26(1), 54-74.
[http://dx.doi.org/10.1016/j.smim.2014.01.001] [PMID: 24552665]
[42]
Newton, K.; Manning, G. Necroptosis and inflammation. Annu. Rev. Biochem., 2016, 85(1), 743-763.
[http://dx.doi.org/10.1146/annurev-biochem-060815-014830] [PMID: 26865533]
[43]
Chong, W.; Shang, L.; Liu, J.; Fang, Z.; Du, F.; Wu, H.; Liu, Y.; Wang, Z.; Chen, Y.; Jia, S.; Chen, L.; Li, L.; Chen, H. m 6 A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer. Theranostics, 2021, 11(5), 2201-2217.
[http://dx.doi.org/10.7150/thno.52717] [PMID: 33500720]
[44]
Hinshaw, D.C.; Shevde, L.A. The tumor microenvironment innately modulates cancer progression. Cancer Res., 2019, 79(18), 4557-4566.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3962] [PMID: 31350295]
[45]
Wu, T.; Dai, Y. Tumor microenvironment and therapeutic response. Cancer Lett., 2017, 387, 61-68.
[http://dx.doi.org/10.1016/j.canlet.2016.01.043] [PMID: 26845449]
[46]
Bejarano, L. Jordāo, M.J.C.; Joyce, J.A. Therapeutic targeting of the tumor microenvironment. Cancer Discov., 2021, 11(4), 933-959.
[http://dx.doi.org/10.1158/2159-8290.CD-20-1808] [PMID: 33811125]
[47]
Xiao, Y.; Yu, D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol. Ther., 2021, 221, 107753.
[http://dx.doi.org/10.1016/j.pharmthera.2020.107753] [PMID: 33259885]
[48]
Taki, M.; Abiko, K.; Ukita, M.; Murakami, R.; Yamanoi, K.; Yamaguchi, K.; Hamanishi, J.; Baba, T.; Matsumura, N.; Mandai, M. Tumor immune microenvironment during epithelial–mesenchymal transition. Clin. Cancer Res., 2021, 27(17), 4669-4679.
[http://dx.doi.org/10.1158/1078-0432.CCR-20-4459] [PMID: 33827891]
[49]
Batlle, E.; Massagué, J. Transforming growth factor-β signaling in immunity and cancer. Immunity, 2019, 50(4), 924-940.
[http://dx.doi.org/10.1016/j.immuni.2019.03.024] [PMID: 30995507]
[50]
Rahma, O.E.; Hodi, F.S. The intersection between tumor angiogenesis and immune suppression. Clin. Cancer Res., 2019, 25(18), 5449-5457.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-1543] [PMID: 30944124]
[51]
Chen, D.S.; Mellman, I. Elements of cancer immunity and the cancer–immune set point. Nature, 2017, 541(7637), 321-330.
[http://dx.doi.org/10.1038/nature21349] [PMID: 28102259]
[52]
Hegde, P.S.; Chen, D.S. Top 10 challenges in cancer immunotherapy. Immunity, 2020, 52(1), 17-35.
[http://dx.doi.org/10.1016/j.immuni.2019.12.011] [PMID: 31940268]
[53]
Clara, J.A.; Monge, C.; Yang, Y.; Takebe, N. Targeting signalling pathways and the immune microenvironment of cancer stem cells — a clinical update. Nat. Rev. Clin. Oncol., 2020, 17(4), 204-232.
[http://dx.doi.org/10.1038/s41571-019-0293-2] [PMID: 31792354]
[54]
Rooney, M.S.; Shukla, S.A.; Wu, C.J.; Getz, G.; Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell, 2015, 160(1-2), 48-61.
[http://dx.doi.org/10.1016/j.cell.2014.12.033] [PMID: 25594174]
[55]
Schumacher, T.N.; Schreiber, R.D. Neoantigens in cancer immunotherapy. Science, 2015, 348(6230), 69-74.
[http://dx.doi.org/10.1126/science.aaa4971] [PMID: 25838375]
[56]
Kristensen, V.N. The antigenicity of the tumor cell — context matters. N. Engl. J. Med., 2017, 376(5), 491-493.
[http://dx.doi.org/10.1056/NEJMcibr1613793] [PMID: 28146670]