Mucosa-like differentiation of head and neck cancer cells is inducible and drives the epigenetic loss of cell malignancy.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
02 Oct 2024
02 Oct 2024
Historique:
received:
15
02
2024
accepted:
11
09
2024
revised:
07
09
2024
medline:
3
10
2024
pubmed:
3
10
2024
entrez:
2
10
2024
Statut:
epublish
Résumé
Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease with high death rates that have remained substantially unaltered for decades. Therefore, new treatment approaches are urgently needed. Human papillomavirus-negative tumors harbor areas of terminally differentiated tissue that are characterized by cornification. Dissecting this intrinsic ability of HNSCC cells to irreversibly differentiate into non-malignant cells may have tumor-targeting potential. We modeled the cornification of HNSCC cells in a primary spheroid model and analyzed the mechanisms underlying differentiation by ATAC-seq and RNA-seq. Results were verified by immunofluorescence using human HNSCC tissue of distinct anatomical locations. HNSCC cell differentiation was accompanied by cell adhesion, proliferation stop, diminished tumor-initiating potential in immunodeficient mice, and activation of a wound-healing-associated signaling program. Small promoter accessibility increased despite overall chromatin closure. Differentiating cells upregulated KRT17 and cornification markers. Although KRT17 represents a basal stem cell marker in normal mucosa, we confirm KRT17 to represent an early differentiation marker in HNSCC tissue. Cornification was frequently found surrounding necrotic areas in human tumors, indicating an involvement of pro-inflammatory stimuli. Indeed, inflammatory mediators activated the differentiation program in primary HNSCC cells. In HNSCC tissue, distinct cell differentiation states were found to create a common tissue architecture in normal mucosa and HNSCCs. Our data demonstrate a loss of cell malignancy upon faithful HNSCC cell differentiation, indicating that targeted differentiation approaches may be therapeutically valuable. Moreover, we describe KRT17 to be a candidate biomarker for HNSCC cell differentiation and early tumor detection.
Identifiants
pubmed: 39358322
doi: 10.1038/s41419-024-07065-y
pii: 10.1038/s41419-024-07065-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
724Subventions
Organisme : Universität Bielefeld (Bielefeld University)
ID : 3-year HNSCC Programm
Organisme : Universität Bielefeld (Bielefeld University)
ID : 3-year HNSCC Programm
Organisme : Universität Bielefeld (Bielefeld University)
ID : 3-year HNSCC Programm
Organisme : Universität Bielefeld (Bielefeld University)
ID : 3-year HNSCC Programm
Organisme : Universität Bielefeld (Bielefeld University)
ID : 3-year HNSCC Programm
Organisme : Universität Bielefeld (Bielefeld University)
ID : 3-year HNSCC Programm
Informations de copyright
© 2024. The Author(s).
Références
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
doi: 10.3322/caac.21492
pubmed: 30207593
Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Pineros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144:1941–53.
doi: 10.1002/ijc.31937
pubmed: 30350310
Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Prim. 2020;6:92.
doi: 10.1038/s41572-020-00224-3
pubmed: 33243986
Denecker G, Ovaere P, Vandenabeele P, Declercq W. Caspase-14 reveals its secrets. J Cell Biol. 2008;180:451–8.
doi: 10.1083/jcb.200709098
pubmed: 18250198
pmcid: 2234247
Enane FO, Saunthararajah Y, Korc M. Differentiation therapy and the mechanisms that terminate cancer cell proliferation without harming normal cells. Cell Death Dis. 2018;9:912.
doi: 10.1038/s41419-018-0919-9
pubmed: 30190481
pmcid: 6127320
Lawson DA, Kessenbrock K, Davis RT, Pervolarakis N, Werb Z. Tumour heterogeneity and metastasis at single-cell resolution. Nat Cell Biol. 2018;20:1349–60.
doi: 10.1038/s41556-018-0236-7
pubmed: 30482943
pmcid: 6477686
Fujii M, Sato T. Defining the role of Lgr5(+) stem cells in colorectal cancer: from basic research to clinical applications. Genome Med. 2017;9:66.
doi: 10.1186/s13073-017-0460-y
pubmed: 28720124
pmcid: 5516356
Ball CR, Oppel F, Ehrenberg KR, Dubash TD, Dieter SM, Hoffmann CM, et al. Succession of transiently active tumor-initiating cell clones in human pancreatic cancer xenografts. EMBO Mol Med. 2017;9:918–32.
doi: 10.15252/emmm.201607354
pubmed: 28526679
pmcid: 5494525
Dubash TD, Hoffmann CM, Oppel F, Giessler KM, Weber S, Dieter SM, et al. Phenotypic differentiation does not affect tumorigenicity of primary human colon cancer initiating cells. Cancer Lett. 2016;371:326–33.
doi: 10.1016/j.canlet.2015.11.037
pubmed: 26679053
Martinez-Ruiz L, Florido J, Rodriguez-Santana C, Lopez-Rodriguez A, Guerra-Librero A, Fernandez-Gil BI, et al. Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stress. Biomed Pharmacother. 2023;167:115518.
doi: 10.1016/j.biopha.2023.115518
pubmed: 37717534
Oppel F, Shao S, Schurmann M, Goon P, Albers AE, Sudhoff H. An effective primary head and neck squamous cell carcinoma in vitro model. Cells. 2019;8:555.
doi: 10.3390/cells8060555
pubmed: 31181618
pmcid: 6628367
Shao S, Scholtz LU, Gendreizig S, Martinez-Ruiz L, Florido J, Escames G, et al. Primary head and neck cancer cell cultures are susceptible to proliferation of Epstein-Barr virus infected lymphocytes. BMC Cancer. 2023;23:47.
doi: 10.1186/s12885-022-10481-y
pubmed: 36639629
pmcid: 9840248
Oppel F, Muller N, Schackert G, Hendruschk S, Martin D, Geiger KD, et al. SOX2-RNAi attenuates S-phase entry and induces RhoA-dependent switch to protease-independent amoeboid migration in human glioma cells. Mol Cancer. 2011;10:137.
doi: 10.1186/1476-4598-10-137
pubmed: 22070920
pmcid: 3228695
Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 2006;9:391–403.
doi: 10.1016/j.ccr.2006.03.030
pubmed: 16697959
van den Ameele J, Krautz R, Cheetham SW, Donovan APA, Llora-Batlle O, Yakob R, et al. Reduced chromatin accessibility correlates with resistance to Notch activation. Nat Commun. 2022;13:2210.
doi: 10.1038/s41467-022-29834-z
pubmed: 35468895
pmcid: 9039071
Blanco MA, Sykes DB, Gu L, Wu M, Petroni R, Karnik R, et al. Chromatin-state barriers enforce an irreversible mammalian cell fate decision. Cell Rep. 2021;37:109967.
doi: 10.1016/j.celrep.2021.109967
pubmed: 34758323
Aughey GN, Estacio Gomez A, Thomson J, Yin H, Southall TD. CATaDa reveals global remodelling of chromatin accessibility during stem cell differentiation in vivo. eLife. 2018;7:e32341.
doi: 10.7554/eLife.32341
pubmed: 29481322
pmcid: 5826290
Kitamura R, Toyoshima T, Tanaka H, Kawano S, Kiyosue T, Matsubara R, et al. Association of cytokeratin 17 expression with differentiation in oral squamous cell carcinoma. J Cancer Res Clin Oncol. 2012;138:1299–310.
doi: 10.1007/s00432-012-1202-6
pubmed: 22466643
pmcid: 3397222
Zhang X, Yin M, Zhang LJ. Keratin 6, 16 and 17-critical barrier alarmin molecules in skin wounds and psoriasis. Cells. 2019;8:807.
doi: 10.3390/cells8080807
pubmed: 31374826
pmcid: 6721482
Mokhtari S. Mechanisms of cyst formation in metastatic lymph nodes of head and neck squamous cell carcinoma. Diagnostic Pathol. 2012;7:6.
doi: 10.1186/1746-1596-7-6
Hanel KH, Cornelissen C, Luscher B, Baron JM. Cytokines and the skin barrier. Int J Mol Sci. 2013;14:6720–45.
doi: 10.3390/ijms14046720
pubmed: 23531535
pmcid: 3645662
Truong AB, Kretz M, Ridky TW, Kimmel R, Khavari PA. p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes Dev. 2006;20:3185–97.
doi: 10.1101/gad.1463206
pubmed: 17114587
pmcid: 1635152
Dejosez M, Dall’Agnese A, Ramamoorthy M, Platt J, Yin X, Hogan M, et al. Regulatory architecture of housekeeping genes is driven by promoter assemblies. Cell Rep. 2023;42:112505.
doi: 10.1016/j.celrep.2023.112505
pubmed: 37182209
pmcid: 10329844
Chen T, Dent SY. Chromatin modifiers and remodellers: regulators of cellular differentiation. Nat Rev Genet. 2014;15:93–106.
doi: 10.1038/nrg3607
pubmed: 24366184
French R, Pauklin S. Epigenetic regulation of cancer stem cell formation and maintenance. Int J cancer. 2021;148:2884–97.
doi: 10.1002/ijc.33398
pubmed: 33197277
Tolomeo M, Cascio A. The multifaced role of STAT3 in cancer and its implication for anticancer therapy. Int J Mol Sci. 2021;22:60.
Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–48.
doi: 10.1038/nrclinonc.2018.8
pubmed: 29405201
pmcid: 5858971
Syed V. TGF-beta signaling in cancer. J Cell Biochem. 2016;117:1279–87.
doi: 10.1002/jcb.25496
pubmed: 26774024
Matherne MG, Phillips ES, Embrey SJ, Burke CM, Machado HL. Emerging functions of C/EBPbeta in breast cancer. Front Oncol. 2023;13:1111522.
doi: 10.3389/fonc.2023.1111522
pubmed: 36761942
pmcid: 9905667
Eferl R, Wagner EF. AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer. 2003;3:859–68.
doi: 10.1038/nrc1209
pubmed: 14668816
Huang Q, Ye M, Li F, Lin L, Hu C. Prognostic and clinicopathological significance of transcription factor c-Jun in hypopharyngeal squamous cell carcinoma: a 3-year follow-up retrospective study. BMC Cancer. 2022;22:1019.
doi: 10.1186/s12885-022-10113-5
pubmed: 36163022
pmcid: 9513886
Baraks G, Tseng R, Pan CH, Kasliwal S, Leiton CV, Shroyer KR, et al. Dissecting the oncogenic roles of keratin 17 in the hallmarks of cancer. Cancer Res. 2022;82:1159–66.
doi: 10.1158/0008-5472.CAN-21-2522
pubmed: 34921015
Escobar-Hoyos LF, Shah R, Roa-Pena L, Vanner EA, Najafian N, Banach A, et al. Keratin-17 promotes p27kip1 nuclear export and degradation and offers potential prognostic utility. Cancer Res. 2015;75:3650–62.
doi: 10.1158/0008-5472.CAN-15-0293
pubmed: 26109559
Li C, Su H, Ruan C, Li X. Keratin 17 knockdown suppressed malignancy and cisplatin tolerance of bladder cancer cells, as well as the activation of AKT and ERK pathway. Folia Histochem Cytobiol. 2021;59:40–8.
doi: 10.5603/FHC.a2021.0005
pubmed: 33577073
Regenbogen E, Mo M, Romeiser J, Shroyer ALW, Escobar-Hoyos LF, Burke S, et al. Elevated expression of keratin 17 in oropharyngeal squamous cell carcinoma is associated with decreased survival. Head Neck. 2018;40:1788–98.
doi: 10.1002/hed.25164
pubmed: 29626364
Dieter SM, Ball CR, Hoffmann CM, Nowrouzi A, Herbst F, Zavidij O, et al. Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. Cell Stem Cell. 2011;9:357–65.
doi: 10.1016/j.stem.2011.08.010
pubmed: 21982235
Clevers H. The intestinal crypt, a prototype stem cell compartment. Cell. 2013;154:274–84.
doi: 10.1016/j.cell.2013.07.004
pubmed: 23870119
Merlos-Suarez A, Barriga FM, Jung P, Iglesias M, Cespedes MV, Rossell D, et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell. 2011;8:511–24.
doi: 10.1016/j.stem.2011.02.020
pubmed: 21419747
Morris JPT, Cano DA, Sekine S, Wang SC, Hebrok M. Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J Clin Investig. 2010;120:508–20.
doi: 10.1172/JCI40045
pubmed: 20071774
pmcid: 2810083
Zimmerman MW, Durbin AD, He S, Oppel F, Shi H, Tao T, et al. Retinoic acid rewires the adrenergic core regulatory circuitry of childhood neuroblastoma. Sci Adv. 2021;7:eabe0834.
doi: 10.1126/sciadv.abe0834
pubmed: 34669465
pmcid: 8528416
Perry CF, Stevens M, Rabie I, Yarker ME, Cochrane J, Perry E, et al. Chemoprevention of head and neck cancer with retinoids: a negative result. Arch Otolaryngol Head Neck Surg. 2005;131:198–203.
doi: 10.1001/archotol.131.3.198
pubmed: 15781758