AbstractHead 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.

摘要头颈部鳞状细胞癌（HNSCC）是一种高度恶性的疾病，死亡率很高，几十年来一直没有改变。因此，迫切需要新的治疗方法。人乳头瘤病毒阴性肿瘤具有以角化为特征的终末分化组织区域。

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.

解剖HNSCC细胞不可逆地分化为非恶性细胞的这种内在能力可能具有肿瘤靶向潜力。我们在初级球体模型中模拟了HNSCC细胞的角质化，并分析了ATAC-seq和RNA-seq分化的潜在机制。使用不同解剖位置的人HNSCC组织通过免疫荧光验证了结果。

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.

HNSCC细胞分化伴随着细胞粘附，增殖停止，免疫缺陷小鼠中肿瘤起始潜力降低以及伤口愈合相关信号程序的激活。尽管整体染色质闭合，但小启动子的可及性增加。分化细胞上调KRT17和角质化标记。

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.

尽管KRT17代表正常粘膜中的基础干细胞标志物，但我们证实KRT17代表HNSCC组织中的早期分化标志物。在人类肿瘤的坏死区域周围经常发现角质化，表明促炎刺激的参与。事实上，炎症介质激活了原代HNSCC细胞的分化程序。

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.

在HNSCC组织中，发现不同的细胞分化状态在正常粘膜和HNSCC中产生共同的组织结构。我们的数据表明，忠实的HNSCC细胞分化后，细胞恶性肿瘤的丧失，表明靶向分化方法可能具有治疗价值。

Moreover, we describe KRT17 .

此外，我们描述了KRT17。

IntroductionHead and neck squamous cell carcinoma (HNSCC) is a highly malignant disease that represents the 6th most common type of cancer in the world. Five-year survival rates of about 50% have remained unchanged for decades [1, 2]. Despite recent advances in molecular targeting and immunotherapy, the prognosis of affected patients remains devastating.

引言头颈部鳞状细胞癌（HNSCC）是一种高度恶性的疾病，代表了世界上第六大最常见的癌症类型。几十年来，约50%的五年生存率保持不变[1，2]。尽管最近在分子靶向和免疫治疗方面取得了进展，但受影响患者的预后仍然具有破坏性。

Even though new approaches in immunotherapy and molecular therapy exist, the standard of care for HNSCC remains surgery, cytotoxic chemotherapy, and radiotherapy. These treatments show limited tumor-specificity and thus frequently damage vital structures in the head and neck area, leading to high morbidity even in long-term survivors [3].

尽管存在免疫疗法和分子疗法的新方法，但HNSCC的护理标准仍然是手术，细胞毒性化疗和放疗。这些治疗显示出有限的肿瘤特异性，因此经常损害头颈部的重要结构，即使在长期幸存者中也会导致高发病率（3）。

Hence, new tumor-specific therapy approaches are urgently needed.Squamous cell carcinomas are characterized by cornified areas detectable by histopathology. Cornification represents the normal differentiation path of keratinocytes in the epidermis and the oral mucosa and ensures the formation of a protective barrier on our body’s surface [4].

。鳞状细胞癌的特征是可通过组织病理学检测到的角质化区域。角质化代表表皮和口腔粘膜中角质形成细胞的正常分化途径，并确保在我们的身体表面形成保护性屏障。

In the malignant context however, “cell differentiation” is defined by how closely a tumor cell resembles its original tissue, but little is known about the potential of long-term repopulating tumor cells to terminally differentiate and lose their malignancy due to epigenetic changes like chromatin remodeling processes.

然而，在恶性背景下，“细胞分化”的定义是肿瘤细胞与其原始组织的相似程度，但对于长期重新填充肿瘤细胞由于表观遗传变化（如染色质重塑过程）而最终分化并丧失其恶性的潜力知之甚少。

It is believed that the malignant cell state may prevent terminal differentiation [5] or causes a plastic differentiation behavior with mixed or reversible differentiation phenotypes [6,7,8,9]. In this study, we have modeled HNSCC cell differentiation, describe differentiation markers, show close structural similarities to the normal tissue counterpart, and established an initial protocol to trigger this process.

据信，恶性细胞状态可能阻止终末分化或导致具有混合或可逆分化表型的塑性分化行为。在这项研究中，我们对HNSCC细胞分化进行了建模，描述了分化标记，显示了与正常组织对应物的紧密结构相似性，并建立了触发该过程的初始方案。

This may provide a.

这可能会提供一个。

Data availability

数据可用性

All sequencing raw data are available on the NCBI Gene Expression Omnibus database under the GEO accession numbers GSE274251 for the ATAC-seq and GSE273699 for the RNA-seq analysis.

所有测序原始数据均可在NCBI Gene Expression Omnibus数据库上获得，其中ATAC-seq的GEO登录号为GSE274251，RNA-seq分析的GSE273699。

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Download referencesAcknowledgementsThe authors thank Thorsten Seidel and the imaging facility of the Faculty for Biology of Bielefeld University for their support of this study. The authors acknowledge the technical NGS team of the Omics CF NGS Unit and CeBiTec. This project was funded by the 3-year head and neck cancer program of the Medical Faculty OWL at Bielefeld University and by the following grants: Ministerio de Ciencia e Innovación/AEI: Agencia Estatal de Investigación/ 10.13039/501100011033/ y financiado por la Unión Europea “NextGenerationEU”/ PRTR (PID2020‐115112RB‐I00)FundingOpen Access funding enabled and organized by Projekt DEAL.Author informationAuthor notesThese authors contributed equally: Felix Oppel, Sarah Gendreizig.Authors and AffiliationsDepartment of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, GermanyFelix Oppel, Sarah Gendreizig, Harkiren Pabla, Lakshna Loganathan, Leonie Hose, Philipp Kühnel, Matthias Schürmann, Flavian Viyof Ful, Lars Uwe Scholtz & Holger SudhoffInstitute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, SpainLaura Martinez-Ruiz, Javier Florido, Alba López-Rodríguez & Germaine EscamesDepartment of Physiology, Faculty of Medicine, University of Granada, Granada, SpainLaura Martinez-Ruiz, Javier Florido, Alba López-Rodríguez & Germaine EscamesCentro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, SpainLaura Martinez-Ruiz, Javier Florido, Alba López-Rodríguez & Germaine EscamesCenter for Biotechnology (CeBiTec), University Hospital OWL.

下载参考文献致谢作者感谢Thorsten Seidel和比勒菲尔德大学生物学系的成像设施对这项研究的支持。作者感谢组学CF NGS部门和CeBiTec的NGS技术团队。该项目由比勒费尔德大学医学院OWL为期3年的头颈癌项目和以下赠款资助：科学和创新部长/AEI：调查机构/10.13039/501100011033/y financiado por la Unión Europea“NextGenerationEU”/PRTR（PID2020-115112RB-I00）资助由Projekt DEAL启用和组织的开放获取资金。作者信息作者注意到这些作者做出了同样的贡献：Felix Oppel，Sarah Gendreizig。作者和附属机构比勒费尔德大学医院耳鼻咽喉头颈外科，比勒费尔德大学医院，比勒费尔德，德国菲利克斯·奥佩尔，莎拉·根德雷泽，哈基伦·帕布拉，拉克什纳·洛加纳坦，莱尼·霍斯，菲利普·库内尔，马蒂亚斯·舒曼，弗拉维安·维约夫·福尔，拉尔斯·乌韦·斯科尔茨和霍尔格·苏霍夫生物技术研究所，生物医学研究中心，格拉纳达大学健康科学技术园，格拉纳达，斯帕因拉·马丁内斯·鲁伊斯，哈维尔·弗洛里多，阿尔巴·洛佩斯Z Rodríguez&GermaineEscamesdepartment of Physiology，Faculty of Medicine，Granada，Granada，SpainLaura Martinez-Ruiz，Javier Florido，Alba López Rodríguez&GermaineEscamescentro de Investigación Biomédica en Red Fragilidad and Envecimiento Saludable（CIBERFES），Instituto de Investigación Biosanitaria（Ibs），Granada，San Cecilio University Hospital，Granada，SpainLaura Martinez-Ruiz，Javier Florido，Alba López Rodríguez＆Germaine EscamesCenter for Biotechnology（CeBiTec），大学医院OWL。

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PubMed Google ScholarContributionsConceptualization, FO; methodology, FO, SG, LMR, KN, JK, DL, and TB; validation, FO, SG, and LMR; formal analysis, FO, SG, and LMR; investigation, FO, SG, LMR, JF, ALR, LH, PK, PS, HP, LL, MS, FVF, JN, DL, and FB; resources, LUS, FB, GE, KN, JK, TB, and HS; data curation, FO and SG; software, SG; writing—original draft preparation, FO and SG; writing-review and editing, FO, SG, LMR, JF, ALR, LH, HP, LL, PK, PS, FVF, JN, MS, PG, LUS, DL, GE, FB, KN, JK, and TB, and HS; visualization, FO, SG, and LMR; supervision, FO, SG, GE, TB, KN, JK, and HS; project administration, FO, LUS, GE, FB, TB, KN, JK, and HS; funding acquisition, FO, PG, GE and HS.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献概念化，FO；方法论，FO，SG，LMR，KN，JK，DL和TB；；形式分析，FO，SG和LMR；调查，FO，SG，LMR，JF，ALR，LH，PK，PS，HP，LL，MS，FVF，JN，DL和FB；资源，LUS，FB，GE，KN，JK，TB和HS；数据管理，FO和SG；软件，SG；撰写原稿准备，FO和SG；写作评论和编辑，FO，SG，LMR，JF，ALR，LH，HP，LL，PK，PS，FVF，JN，MS，PG，LUS，DL，GE，FB，KN，JK和TB，以及HS；可视化，FO，SG和LMR；监督、FO、SG、GE、TB、KN、JK和HS；项目管理、FO、LUS、GE、FB、TB、KN、JK和HS；资金收购、FO、PG、GE和HS。通讯作者通讯。

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Reprints and permissionsAbout this articleCite this articleOppel, F., Gendreizig, S., Martinez-Ruiz, L. et al. Mucosa-like differentiation of head and neck cancer cells is inducible and drives the epigenetic loss of cell malignancy.

转载和许可本文引用本文Oppel，F.，Gendreizig，S.，Martinez-Ruiz，L。等人。头颈癌细胞的粘膜样分化是可诱导的，并驱动细胞恶性肿瘤的表观遗传损失。

Cell Death Dis 15, 724 (2024). https://doi.org/10.1038/s41419-024-07065-yDownload citationReceived: 15 February 2024Revised: 07 September 2024Accepted: 11 September 2024Published: 02 October 2024DOI: https://doi.org/10.1038/s41419-024-07065-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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