BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

New established cell lines from undifferentiated pleomorphic sarcoma for in vivo study

  • Eun-Young Lee (Cancer Microenvironment Branch, Division of Cancer Biology, Research Institute, National Cancer Center) ;
  • Young-Ho Kim (Diagnostics and Therapeutics Technology Branch, Division of Technology Convergence, Research Institute, National Cancer Center) ;
  • Md Abu Rayhan (Cancer Microenvironment Branch, Division of Cancer Biology, Research Institute, National Cancer Center) ;
  • Hyun Guy Kang (Department of Cancer Biomedical Science, NCC-GCSP, National Cancer Center) ;
  • June Hyuk Kim (Department of Cancer Biomedical Science, NCC-GCSP, National Cancer Center) ;
  • Jong Woong Park (Department of Orthopaedic Surgery, Hospital, National Cancer Center) ;
  • Seog-Yun Park (Department of Pathology, National Cancer Center Hospital) ;
  • So Hee Lee (Cancer Microenvironment Branch, Division of Cancer Biology, Research Institute, National Cancer Center) ;
  • Hye Jin You (Cancer Microenvironment Branch, Division of Cancer Biology, Research Institute, National Cancer Center)
  • Received : 2022.12.28
  • Accepted : 2023.02.14
  • Published : 2023.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

As a high-grade soft-tissue sarcoma (STS), undifferentiated pleomorphic sarcoma (UPS) is highly recurrent and malignant. UPS is categorized as a tumor of uncertain differentiation and has few options for treatment due to its lack of targetable genetic alterations. There are also few cell lines that provide a representative model for UPS, leading to a dearth of experimental research. Here, we established and characterized new cell lines derived from two recurrent UPS tissues. Cells were obtained from UPS tissues by mincing, followed by extraction or dissociation using enzymes and culture in a standard culture environment. Cells were maintained for several months without artificial treatment, and some cell clones were found to be tumorigenic in an immunodeficient mouse model. Interestingly, some cells formed tumors in vivo when injected after aggregation in a non-adherent culture system for 24 h. The tissues from in vivo study and tissues from patients shared common histological characteristics. Pathways related to the cell cycle, such as DNA replication, were enriched in both cell clones. Pathways related to cell-cell adhesion and cell-cell signaling were also enriched, suggesting a role of the mesenchymal-to-epithelial transition for tumorigenicity in vivo. These new UPS cell lines may facilitate research to identify therapeutic strategies for UPS.

Keywords

Acknowledgement

This work was supported in part by National Cancer Center Grant NCC-2110521 (to H.J.Y.), NCC-2110330 (to H.J.Y.), 1810865 (to H.J.Y.) and National Research Foundation of Korea Grant funded by the Korea Government (MSIP, South Korea) (NRF-2021R1A2C2014147 to H.J.Y.). We thank Tae Sik Kim of the FACS core (National Cancer Center) and Mi Sun Park of the Animal Laboratory core (National Cancer Center) for their expert assistance and helpful suggestions. We thank Dr. Eun Kyung Hong (National Cancer Center Hospital) for her expert and Minjeong Kim (National Cancer Center) and Yoon Hyuk Nam (National Cancer Center-Graduate School of Cancer Science and Policy) for his assistance.

References

  1. WCoTEB (2020) Soft tissues and bone tumours; in World Health Organization, IARC, Switzerland 
  2. Choi JH and Ro JY (2021) The 2020 WHO classification of tumors of soft tissue: selected changes and new entities. Adv Anat Pathol 28, 44-58  https://doi.org/10.1097/PAP.0000000000000284
  3. Steele CD, Tarabichi M, Oukrif D et al (2019) Undifferentiated sarcomas develop through distinct evolutionary pathways. Cancer Cell 35, 441-456 e448 
  4. Steele CD and Pillay N (2020) The genomics of undifferentiated sarcoma of soft tissue: progress, challenges and opportunities. Semin Cancer Biol 61, 42-55  https://doi.org/10.1016/j.semcancer.2019.11.009
  5. Fletcher CD, Dal Cin P, de Wever I et al (1999) Correlation between clinicopathological features and karyotype in spindle cell sarcomas. A report of 130 cases from the CHAMP study group. Am J Pathol 154, 1841-1847  https://doi.org/10.1016/S0002-9440(10)65441-7
  6. Kim J, Kim JH, Kang HG et al (2018) Integrated molecular characterization of adult soft tissue sarcoma for therapeutic targets. BMC Med Genet 19, 216 
  7. TCGA Research Network (2017) Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell 171, 950-965 e928 
  8. Bui NQ, Przybyl J, Trabucco SE et al (2019) A clinicogenomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis. Clin Sarcoma Res 9, 12 
  9. Gengenbacher N, Singhal M and Augustin HG (2017) Preclinical mouse solid tumour models: status quo, challenges and perspectives. Nat Rev Cancer 17, 751-765  https://doi.org/10.1038/nrc.2017.92
  10. Dodd RD, Mito JK and Kirsch DG (2010) Animal models of soft-tissue sarcoma. Dis Model Mech 3, 557-566  https://doi.org/10.1242/dmm.005223
  11. Kirsch DG, Dinulescu DM, Miller JB et al (2007) A spatially and temporally restricted mouse model of soft tissue sarcoma. Nat Med 13, 992-997  https://doi.org/10.1038/nm1602
  12. Sachdeva M, Mito JK, Lee CL et al (2014) MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes. J Clin Invest 124, 4305-4319  https://doi.org/10.1172/JCI77116
  13. Nacev BA, Sanchez-Vega F, Smith SA et al (2022) Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets. Nat Commun 13, 3405 
  14. Salawu A, Fernando M, Hughes D et al (2016) Establishment and molecular characterisation of seven novel soft-tissue sarcoma cell lines. Br J Cancer 115, 1058-1068  https://doi.org/10.1038/bjc.2016.259
  15. Amm HM, DeVilliers P, Srivastava AR, Diniz MG, Siegal GP and MacDougall M (2020) Mandibular undifferentiated pleomorphic sarcoma: molecular analysis of a primary cell population. Clin Exp Dent Res 6, 495-505  https://doi.org/10.1002/cre2.301
  16. Bhalla AD, Landers SM, Singh AK et al (2022) Experimental models of undifferentiated pleomorphic sarcoma and malignant peripheral nerve sheath tumor. Lab Invest 102, 658-666  https://doi.org/10.1038/s41374-022-00734-6
  17. Ono T, Yoshimatsu Y, Noguchi R et al (2022) Establishment and characterization of NCC-UPS4-C1: a novel cell line of undifferentiated pleomorphic sarcoma from a patient with Li-Fraumeni syndrome. Hum Cell 35, 756-766  https://doi.org/10.1007/s13577-022-00671-y
  18. Lee EY, Kim M, Choi BK, Kim DH, Choi I and You HJ (2021) TJP1 Contributes to tumor progression through supporting cell-cell aggregation and communicating with tumor microenvironment in leiomyosarcoma. Mol Cells 44, 784-794  https://doi.org/10.14348/molcells.2021.0130
  19. Lower SS, McGurk MP, Clark AG and Barbash DA (2018) Satellite DNA evolution: old ideas, new approaches. Curr Opin Genet Dev 49, 70-78  https://doi.org/10.1016/j.gde.2018.03.003
  20. Sinicrope FA and Sargent DJ (2012) Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive, and therapeutic implications. Clin Cancer Res 18, 1506-1512  https://doi.org/10.1158/1078-0432.CCR-11-1469
  21. Li K, Luo H, Huang L, Luo H and Zhu X (2020) Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int 20, 16 
  22. Karamitopoulou E, Andreou A, Wenning AS, Gloor B and Perren A (2022) High tumor mutational burden (TMB) identifies a microsatellite stable pancreatic cancer subset with prolonged survival and strong anti-tumor immunity. Eur J Cancer 169, 64-73  https://doi.org/10.1016/j.ejca.2022.03.033
  23. Campanella NC, Penna V, Ribeiro G, Abrahao-Machado LF, Scapulatempo-Neto C and Reis RM (2015) Absence of microsatellite instability in soft tissue sarcomas. Pathobiology 82, 36-42  https://doi.org/10.1159/000369906
  24. Savina M, Le Cesne A, Blay JY et al (2017) Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study. BMC Med 15, 78 
  25. Galmarini CM, Mackey JR and Dumontet C (2002) Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol 3, 415-424  https://doi.org/10.1016/S1470-2045(02)00788-X
  26. Svancarova L, Blay JY, Judson IR et al (2002) Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 38, 556-559  https://doi.org/10.1016/S0959-8049(01)00408-7
  27. Schoenfeld JD, Sibenaller ZA, Mapuskar KA et al (2018) Redox active metals and H2O2 mediate the increased efficacy of pharmacological ascorbate in combination with gemcitabine or radiation in pre-clinical sarcoma models. Redox Biol 14, 417-422  https://doi.org/10.1016/j.redox.2017.09.012
  28. Ge SX, Son EW and Yao R (2018) iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data. BMC Bioinformatics 19, 534 
  29. Jolliffe IT and Cadima J (2016) Principal component analysis: a review and recent developments. Philos Trans A Math Phys Eng Sci 374, 20150202 
  30. Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP and Tamayo P (2015) The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 1, 417-425  https://doi.org/10.1016/j.cels.2015.12.004
  31. Borst P and Schinkel AH (2013) P-glycoprotein ABCB1: a major player in drug handling by mammals. J Clin Invest 123, 4131-4133  https://doi.org/10.1172/JCI70430
  32. Jegal ME, Jung SY, Han YS and Kim YJ (2019) C-terminal truncated HBx reduces doxorubicin cytotoxicity via ABCB1 upregulation in Huh-7 hepatocellular carcinoma cells. BMB Rep 52, 330-335  https://doi.org/10.5483/BMBRep.2019.52.5.312
  33. Cole SP (2014) Multidrug resistance protein 1 (MRP1, ABCC1), a "multitasking" ATP-binding cassette (ABC) transporter. J Biol Chem 289, 30880-30888  https://doi.org/10.1074/jbc.R114.609248
  34. Doyle L and Ross DD (2003) Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22, 7340-7358  https://doi.org/10.1038/sj.onc.1206938
  35. Roh YG, Mun MH, Jeong MS et al (2018) Drug resistance of bladder cancer cells through activation of ABCG2 by FOXM1. BMB Rep 51, 98-103  https://doi.org/10.5483/BMBRep.2018.51.2.222
  36. Bentires-Alj M, Barbu V, Fillet M et al (2003) NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 22, 90-97 https://doi.org/10.1038/sj.onc.1206056