現今，化療藥物仍是治療頭頸癌最有效益的治療方式。部分的頭頸癌患者在接受一系列的化療療程之後得以暫時痊癒，但是一段時間之後仍有可能會出現復發合併遠端轉移。為了深入探討此現象，實驗室建立化療後存活之頭頸癌細胞藉以探討癌症轉移現象，並且於先前研究發現該細胞會大量表達五聚環蛋白3（PTX3）與確認五聚環蛋白3得以調控癌症轉移。本研究藉由細胞計數、β-半乳糖苷酶染色、細胞增生與細胞存活率試驗等方法分別分析化療後存活之頭頸癌細胞與復發之頭頸癌細胞特性；透過癌細胞侵襲、癌細胞球體形成、血管內皮細胞通透性與血管生成試驗，評估化療後存活之頭頸癌細胞培養基中的五聚環蛋白3是否促進癌細胞與血管內皮細胞的交互作用，進一步提升癌細胞遠端轉移的能力。化療後存活之頭頸癌細胞呈現低度增生與休眠特徵，並且展現更強的轉移、癌症幹細胞及抗藥等特性，而復發之頭頸癌細胞則無法維持該特性。化療後存活之頭頸癌細胞培養基得以提升頭頸癌細胞面臨失巢凋亡之存活能力，但是無法增加血管內皮細胞通透性與引發血管增生；化療後存活之頭頸癌細胞釋放之五聚環蛋白3得以增加癌細胞侵襲能力。除此之外，血管內皮細胞培養基得以促進化療後存活之頭頸癌細胞展現更強的侵襲與球體形成能力，有利於化療後存活之頭頸癌細胞進行遠端轉移。本研究結果顯示，化療後存活之頭頸癌細胞展現低度增生與休眠特性，同時該細胞所釋放之五聚環蛋白3得以提升癌細胞的轉移能力，期許透過開發得以抑制五聚環蛋白3表現與作用之藥物得以提升頭頸癌患者的治療效益與預後。

Chemotherapy is the major effective treatment of head and neck squamous cell carcinoma (HNSCC). However, HNSCC patients still suffer from recurrence and distal metastasis after chemotherapy. We have established post-chemotherapy surviving HNSCC (HNSCC-S) to study tumor metastasis and found pentraxin 3 (PTX3) was upregulated in HNSCC-S, which played a critical role in metastasis in our previous research. In order to realize the characteristics of HNSCC-S and recurrent HNSCC, cell population counting, β-galactosidase staining, CFSE staining and MTT assay were conducted. To explore the roles of HNSCC-S-derived PTX3 in distal metastasis and its interactions with endothelial cells, conditioned medium (CM) derived from HNSCC-S or endothelial cells was treated on HNSCC cells and endothelial cells or HNSCC-S, respectively, and evaluate the effects of cancer metastasis and their crosstalk by invasion, spheroid formation, permeability and tube formation assay. HNSCC-S displayed in low proliferative state, dormancy, high metastatic and acquired stemness and drug resistance properties. On the contrary, recurrent HNSCC could not sustain those effects. HNSCC-S-derived CM could improve the survival of HNSCC as facing anoikis; but could not induce vascular leakage and facilitate angiogenesis. HNSCC-S-derived PTX3 promoted the metastasis of HNSCC by increasing its invasion ability. In addition, endothelial cells-derived CM would enhance the distal metastasis of HNSCC-S through regulating its invasion and spheroid formation abilities. In summary, low proliferative HNSCC-S stayed in dormancy and it-derived PTX3 promoted the metastasis of HNSCC. Targeting PTX3 may result in a better outcome for HNSCC patients.

1. Health Promotion Administration T. Ministry of Health and Welfare Releases Cancer Incidence Data in 2018. Updated 2023/09/27. https://www.hpa.gov.tw/EngPages/Detail.aspx?nodeid=1051&pid=14780
2. Barsouk A, Aluru JS, Rawla P, Saginala K, Barsouk A. Epidemiology, risk factors, and prevention of head and neck squamous cell carcinoma. Medical Sciences. 2023;11(2):42. doi:10.3390/medsci11020042
3. Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nature Reviews Disease Primers. 2020;6(1)doi:10.1038/s41572-020-00224-3
4. Hedberg ML, Goh G, Chiosea SI, et al. Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma. Journal of Clinical Investigation. 2015;126(1):169-180. doi:10.1172/jci82066
5. Lee YS, Johnson DE, Grandis JR. An update: emerging drugs to treat squamous cell carcinomas of the head and neck. Expert Opinion on Emerging Drugs. 2018;23(4):283-299. doi:10.1080/14728214.2018.1543400
6. Chang J-H, Wu C-C, Yuan KS-P, Wu ATH, Wu S-Y. Locoregionally recurrent head and neck squamous cell carcinoma: incidence, survival, prognostic factors, and treatment outcomes. Oncotarget. 2017;8(33):55600-55612. doi:10.18632/oncotarget.16340
7. Haring CT, Kana LA, Dermody SM, et al. Patterns of recurrence in head and neck squamous cell carcinoma to inform personalized surveillance protocols. Cancer. 2023;129(18):2817-2827. doi:10.1002/cncr.34823
8. He J, Qiu Z, Fan J, Xie X, Sheng Q, Sui X. Drug tolerant persister cell plasticity in cancer: a revolutionary strategy for more effective anticancer therapies. Signal Transduction and Targeted Therapy. 2024;9(1)doi:10.1038/s41392-024-01891-4
9. Chen M, Mainardi S, Lieftink C, et al. Targeting of vulnerabilities of drug-tolerant persisters identified through functional genetics delays tumor relapse. Cell Rep Med. Mar 19 2024;5(3):101471. doi:10.1016/j.xcrm.2024.101471
10. Lin H, Wang L, Chen H, et al. Mitochondrial fatty acid oxidation as the target for blocking therapy-resistance and inhibiting tumor recurrence: The proof-of-principle model demonstrated for ovarian cancer cells. Journal of Advanced Research. 2025/03/17/ 2025;doi:https://doi.org/10.1016/j.jare.2025.03.026
11. Liu Y, Azizian NG, Sullivan DK, Li Y. mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters. Nat Commun. Nov 17 2022;13(1):7047. doi:10.1038/s41467-022-34890-6
12. Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduction and Targeted Therapy. 2020;5(1)doi:10.1038/s41392-020-0134-x
13. Mittal V. Epithelial mesenchymal transition in tumor metastasis. Annual Review of Pathology: Mechanisms of Disease. 2018;13(1):395-412. doi:10.1146/annurev-pathol-020117-043854
14. Peinado H, Zhang H, Matei IR, et al. Pre-metastatic niches: organ-specific homes for metastases. Nature Reviews Cancer. 2017;17(5):302-317. doi:10.1038/nrc.2017.6
15. Dong Q, Liu X, Cheng K, Sheng J, Kong J, Liu T. Pre-metastatic niche formation in different organs induced by tumor extracellular vesicles. Frontiers in Cell and Developmental Biology. 2021;9doi:10.3389/fcell.2021.733627
16. Li K, Xue W, Lu Z, et al. Tumor-derived exosomal ADAM17 promotes pre-metastatic niche formation by enhancing vascular permeability in colorectal cancer. Journal of Experimental & Clinical Cancer Research. 2024;43(1)doi:10.1186/s13046-024-02991-3
17. Zeng Z, Li Y, Pan Y, et al. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nature Communications. 2018;9(1)doi:10.1038/s41467-018-07810-w
18. Cohen N, Mundhe D, Deasy SK, et al. Breast cancer–secreted factors promote lung metastasis by signaling systemically to induce a fibrotic premetastatic niche. Cancer Research. 2023;83(20):3354-3367. doi:10.1158/0008-5472.can-22-3707
19. Ji Q, Zhou L, Sui H, et al. Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation. Nature Communications. 2020;11(1)doi:10.1038/s41467-020-14869-x
20. Costa-Silva B, Aiello NM, Ocean AJ, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nature Cell Biology. 2015;17(6):816-826. doi:10.1038/ncb3169
21. Wang J, Luo Z, Lin L, et al. Anoikis-associated lung cancer metastasis: mechanisms and therapies. Cancers. 2022;14(19):4791. doi:10.3390/cancers14194791
22. Yu Usami KI, Sunao Sato, Mitsunobu Kishino, Megumi Kiryu, Yuzo Ogawa, Masaya Okura, Yasuo Fukuda, Satoru Toyosawa. Intercellular adhesion molecule-1 (ICAM-1) expression correlates with oral cancer progression and induces macrophage/cancer cell adhesion. International journal of cancer. 2013;133(3):568–578. doi:10.1002/ijc.28066
23. Zhang B, Li X, Tang K, et al. Adhesion to the brain endothelium selects breast cancer cells with brain metastasis potential. International Journal of Molecular Sciences. 2023;24(8):7087. doi:10.3390/ijms24087087
24. Di Martino JS, Akhter T, Bravo-Cordero JJ. Remodeling the ECM: Implications for metastasis and tumor dormancy. Cancers (Basel). Sep 30 2021;13(19)doi:10.3390/cancers13194916
25. Park S-Y, Nam J-S. The force awakens: metastatic dormant cancer cells. Experimental & Molecular Medicine. 2020/04/01 2020;52(4):569-581. doi:10.1038/s12276-020-0423-z
26. Sriratanasak N, Chunhacha P, Ei ZZ, Chanvorachote P. Cisplatin induces senescent lung cancer cell-mediated stemness induction via GRP78/Akt-dependent mechanism. Biomedicines. 2022;10(11):2703. doi:10.3390/biomedicines10112703
27. Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer. Nature Reviews Cancer. 2022;22(6):340-355. doi:10.1038/s41568-022-00450-9
28. Kurppa KJ, Liu Y, To C, et al. Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell. 2020/01/13/ 2020;37(1):104-122.e12. doi:https://doi.org/10.1016/j.ccell.2019.12.006
29. Sun Y, Chen Y, Liu Z, et al. Mitophagy-mediated tumor dormancy protects cancer cells from chemotherapy. Biomedicines. 2024;12(2). doi:10.3390/biomedicines12020305
30. Esmatabadi MJD, Bakhshinejad B, Motlagh FM, Babashah S, Sadeghizadeh M. Therapeutic resistance and cancer recurrence mechanisms: Unfolding the story of tumour coming back. Journal of Biosciences. 2016/09/01 2016;41(3):497-506. doi:10.1007/s12038-016-9624-y
31. Probst AV, Dunleavy E, Almouzni G. Epigenetic inheritance during the cell cycle. Nature Reviews Molecular Cell Biology. 2009/03/01 2009;10(3):192-206. doi:10.1038/nrm2640
32. Darwiche N. Epigenetic mechanisms and the hallmarks of cancer: an intimate affair. Am J Cancer Res. 2020;10(7):1954-1978.
33. Clements ME, Holtslander L, Edwards C, et al. HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer. Oncogene. 2021/08/01 2021;40(34):5314-5326. doi:10.1038/s41388-021-01931-1
34. Cuesta-Borràs E, Salvans C, Arqués O, et al. DPPA3-HIF1α axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype. Cell Rep. Aug 29 2023;42(8):112927. doi:10.1016/j.celrep.2023.112927
35. Evron E, Umbricht CB, Korz D, et al. Loss of cyclin D2 expression in the majority of breast cancers is associated with promoter hypermethylation. Cancer Res. Mar 15 2001;61(6):2782-7.
36. Henrique R, Costa VL, Cerveira N, et al. Hypermethylation of Cyclin D2 is associated with loss of mRNA expression and tumor development in prostate cancer. Journal of Molecular Medicine. 2006/11/01 2006;84(11):911-918. doi:10.1007/s00109-006-0099-4
37. Kudo R, Safonov A, Jones C, et al. Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion. Cancer Cell. 2024/11/11/ 2024;42(11):1919-1935.e9. doi:https://doi.org/10.1016/j.ccell.2024.09.009
38. Li G, Guo X, Chen M, et al. Prevalence and spectrum of AKT1, PIK3CA, PTEN and TP53 somatic mutations in Chinese breast cancer patients. PLOS ONE. 2018;13(9):e0203495. doi:10.1371/journal.pone.0203495
39. Páez D, Labonte MJ, Bohanes P, et al. Cancer dormancy: A model of early dissemination and late cancer recurrence. Clinical Cancer Research. 2012;18(3):645-653. doi:10.1158/1078-0432.Ccr-11-2186
40. Di Martino JS, Nobre AR, Mondal C, et al. A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy. Nature Cancer. 2022/01/01 2022;3(1):90-107. doi:10.1038/s43018-021-00291-9
41. Garlanda C, Bottazzi B, Magrini E, Inforzato A, Mantovani A. PTX3, a humoral pattern recognition molecule, in innate immunity, tissue repair, and cancer. Physiol Rev. Apr 1 2018;98(2):623-639. doi:10.1152/physrev.00016.2017
42. Doni A, Garlanda C, Mantovani A. PTX3 orchestrates tissue repair. Oncotarget. 2015;6(31)
43. Chi JY, Hsiao YW, Liang HY, et al. Blockade of the pentraxin 3/CD44 interaction attenuates lung injury-induced fibrosis. Clin Transl Med. Nov 2022;12(11):e1099. doi:10.1002/ctm2.1099
44. Chang WC, Wu SL, Huang WC, et al. PTX3 gene activation in EGF-induced head and neck cancer cell metastasis. Oncotarget. Apr 10 2015;6(10):7741-57. doi:10.18632/oncotarget.3482
45. Ying T-H, Lee C-H, Chiou H-L, et al. Knockdown of Pentraxin 3 suppresses tumorigenicity and metastasis of human cervical cancer cells. Scientific Reports. 2016/07/05 2016;6(1):29385. doi:10.1038/srep29385
46. Carrizzo A, Lenzi P, Procaccini C, et al. Pentraxin 3 induces vascular endothelial dysfunction through a P-selectin/matrix metalloproteinase-1 pathway. Circulation. 2015;131(17):1495-1505. doi:doi:10.1161/CIRCULATIONAHA.114.014822
47. Shih-Hung Chan J-PT, Chih-Jie Shen, Yu-Han Liao, Ben-Kuen Chen. Oleate-induced PTX3 promotes head and neck squamous cell carcinoma metastasis through the up-regulation of vimentin. Oncotarget. 2017;8(25):15. doi: 10.18632/oncotarget.17326
48. Hsiao YW, Chi JY, Li CF, et al. Disruption of the pentraxin 3/CD44 interaction as an efficient therapy for triple‐negative breast cancers. Clinical and Translational Medicine. 2022;12(1)doi:10.1002/ctm2.724
49. 鐘明耀, Chung M-Y. 探討五聚環蛋白3在化療藥物後治療後的頭頸部鱗狀癌細胞中調控腫瘤轉移能力所扮演的角色 = Investigating the role of PTX3 in the regulation of tumor metastasis in post-chemotherapy surviving HNSCC cells / 鐘明耀(Ming-Yao Chung)撰. 國立成功大學藥理學研究所; 2022.
50. Tichet M, Prod’Homme V, Fenouille N, et al. Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis. Nature Communications. 2015;6(1):6993. doi:10.1038/ncomms7993
51. Zhang P, Goodrich C, Fu C, Dong C. Melanoma upregulates ICAM-1 expression on endothelial cells through engagement of tumor CD44 with endothelial E-selectin and activation of a PKCα-p38-SP-1 pathway. Faseb j. Nov 2014;28(11):4591-609. doi:10.1096/fj.11-202747
52. Lei X, Li Z, Huang M, et al. Gli1-mediated tumor cell-derived bFGF promotes tumor angiogenesis and pericyte coverage in non-small cell lung cancer. Journal of Experimental & Clinical Cancer Research. 2024/03/16 2024;43(1):83. doi:10.1186/s13046-024-03003-0
53. Liu Z-L, Chen H-H, Zheng L-L, Sun L-P, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduction and Targeted Therapy. 2023/05/11 2023;8(1):198. doi:10.1038/s41392-023-01460-1
54. Labelle M, Hynes RO. The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discov. Dec 2012;2(12):1091-9. doi:10.1158/2159-8290.Cd-12-0329
55. Dewhirst MW, Secomb TW. Transport of drugs from blood vessels to tumour tissue. Nature Reviews Cancer. 2017/12/01 2017;17(12):738-750. doi:10.1038/nrc.2017.93
56. Soltani M, Chen P. Numerical modeling of fluid flow in solid tumors. PLOS ONE. 2011;6(6):e20344. doi:10.1371/journal.pone.0020344
57. Tamura T, Imai J, Matsumoto A, et al. Organ distribution of cisplatin after intraperitoneal administration of cisplatin-loaded microspheres. Eur J Pharm Biopharm. Jul 2002;54(1):1-7. doi:10.1016/s0939-6411(02)00037-1
58. El-Kareh AW, Secomb TW. A theoretical model for intraperitoneal delivery of cisplatin and the effect of hyperthermia on drug penetration distance. Neoplasia. Mar-Apr 2004;6(2):117-27. doi:10.1593/neo.03205
59. Zhou W, Miranda, Min Y, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014;25(4):501-515. doi:10.1016/j.ccr.2014.03.007
60. Rathore M, Girard C, Ohanna M, et al. Cancer cell-derived long pentraxin 3 (PTX3) promotes melanoma migration through a toll-like receptor 4 (TLR4)/NF-κB signaling pathway. Oncogene. Jul 2019;38(30):5873-5889. doi:10.1038/s41388-019-0848-9
61. Zhang JC, Tao T, Liu JQ. [PTX3 promotes proliferation, invasion and drug resistance of neuroblastoma cells in children by regulating TLR4/NF-κB signaling pathway]. Zhonghua Zhong Liu Za Zhi. Jan 23 2021;43(1):118-125. doi:10.3760/cma.j.cn112152-20191227-00844
62. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. Feb 7 2020;367(6478)doi:10.1126/science.aau6977
63. 許卉婕, Hii H-J. 探討順鉑治療後存活頭頸部鱗狀癌細胞中的代謝重整 = Investigating the metabolic reprogramming of surviving cells in cisplatin-treated head and neck squamous cell carcinoma / 許卉婕(Hui-Jie Hii)撰. 國立成功大學藥理學研究所; 2023.
64. Pu Y, Li L, Peng H, et al. Drug-tolerant persister cells in cancer: the cutting edges and future directions. Nature Reviews Clinical Oncology. 2023;20(11):799-813. doi:10.1038/s41571-023-00815-5
65. Wu YC, Huang CS, Hsieh MS, et al. Targeting of FSP1 regulates iron homeostasis in drug-tolerant persister head and neck cancer cells via lipid-metabolism-driven ferroptosis. Aging (Albany NY). Jan 10 2024;16(1):627-647. doi:10.18632/aging.205409
66. Chen TM, Huang CM, Setiawan SA, Hsieh MS, Sheen CC, Yeh CT. KDM5D Histone Demethylase Identifies Platinum-Tolerant Head and Neck Cancer Cells Vulnerable to Mitotic Catastrophe. Int J Mol Sci. Mar 10 2023;24(6)doi:10.3390/ijms24065310
67. Chi JY, Hsiao YW, Li CF, et al. Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers. Oncotarget. Sep 15 2015;6(27):23987-4001. doi:10.18632/oncotarget.4364
68. He M, Zhou X, Wang X. Glycosylation: mechanisms, biological functions and clinical implications. Signal Transduction and Targeted Therapy. 2024/08/05 2024;9(1):194. doi:10.1038/s41392-024-01886-1
69. Inforzato A, Reading PC, Barbati E, Bottazzi B, Garlanda C, Mantovani A. The "sweet" side of a long pentraxin: how glycosylation affects PTX3 functions in innate immunity and inflammation. Front Immunol. 2012;3:407. doi:10.3389/fimmu.2012.00407
70. Zhong B, Cheng B, Huang X, et al. Colorectal cancer-associated fibroblasts promote metastasis by up-regulating LRG1 through stromal IL-6/STAT3 signaling. Cell Death & Disease. 2021/12/20 2021;13(1):16. doi:10.1038/s41419-021-04461-6
71. Liu L, Ba Y, Yang S, et al. FOS-driven inflammatory CAFs promote colorectal cancer liver metastasis via the SFRP1-FGFR2-HIF1 axis. Theranostics. 2025;15(10):4593-4613. doi:10.7150/thno.111625
72. Maishi N, Ohba Y, Akiyama K, et al. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan. Scientific Reports. 2016/06/13 2016;6(1):28039. doi:10.1038/srep28039
73. Linde N, Fluegen G, Aguirre-Ghiso JA. The relationship between dormant cancer cells and their microenvironment. Adv Cancer Res. 2016;132:45-71. doi:10.1016/bs.acr.2016.07.002
74. Krishnamurthy S, Dong Z, Vodopyanov D, et al. Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells. Cancer Research. 2010;70(23):9969-9978. doi:10.1158/0008-5472.can-10-1712
75. Chen Y, Zhu G, Wu K, et al. FGF2-mediated reciprocal tumor cell-endothelial cell interplay contributes to the growth of chemoresistant cells: a potential mechanism for superficial bladder cancer recurrence. Tumor Biology. 2016/04/01 2016;37(4):4313-4321. doi:10.1007/s13277-015-4214-4
76. Yao M, Yu E, Staggs V, Fan F, Cheng N. Elevated expression of chemokine C-C ligand 2 in stroma is associated with recurrent basal-like breast cancers. Modern Pathology. 2016;29(8):810-823. doi:10.1038/modpathol.2016.78
77. Wang HH, Cui YL, Zaorsky NG, et al. Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy. Cancer Lett. Jun 1 2016;375(2):349-359. doi:10.1016/j.canlet.2016.02.033
78. Nair S, Bonner JA, Bredel M. EGFR mutations in head and neck squamous cell carcinoma. Int J Mol Sci. Mar 30 2022;23(7)doi:10.3390/ijms23073818
79. Liu D, Aguirre Ghiso J, Estrada Y, Ossowski L. EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell. Jun 2002;1(5):445-57. doi:10.1016/s1535-6108(02)00072-7
80. Sharma SV, Lee DY, Li B, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. Apr 2 2010;141(1):69-80. doi:10.1016/j.cell.2010.02.027
81. Shi R, Farnsworth DA, Febres-Aldana CA, et al. Drug tolerance and persistence to EGFR inhibitor treatment are mediated by an ILK-SFK-YAP signaling axis in lung adenocarcinoma. Oncogene. 2025/05/31 2025;doi:10.1038/s41388-025-03461-6
82. Roesch A, Fukunaga-Kalabis M, Schmidt EC, et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell. 2010/05/14/ 2010;141(4):583-594. doi:https://doi.org/10.1016/j.cell.2010.04.020
83. Roesch A, Vultur A, Bogeski I, et al. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh Cells. Cancer Cell. 2013/06/10/ 2013;23(6):811-825. doi:https://doi.org/10.1016/j.ccr.2013.05.003
84. Hangauer MJ, Viswanathan VS, Ryan MJ, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. Nov 9 2017;551(7679):247-250. doi:10.1038/nature24297