Integrin alpha 7: Co-regulatory mechanisms of gene expression, gene accessibility and genotoxic resistance in head and neck squamous cell carcinoma cells

整合素α7：头颈鳞状细胞癌细胞基因表达、基因可及性和基因毒性抗性的协同调节机制

• 批准号: 528501357
• 负责人: Professor Dr. Nils Cordes
• 金额: --
• 依托单位: OncoRay - Zentrum für Medizinische Strahlenforschung in der Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/528501357?language=en
• 关键词: Integrin; alpha; Co; regulatory; mechanisms

Head and neck squamous cell carcinoma (HNSCC) is a cancer of unmet need. Despite great efforts to optimize therapy, locoregional control and overall survival have remained stable over the past three decades. A variety of genetic, epigenetic, and microenvironmental factors fundamentally influence the response of HNSCC to therapy. A key determinant of resistance is integrin-mediated cell-extracellular matrix (ECM) interaction, whose disruption has been shown to elicit sensitization to radiotherapy, chemotherapy, or molecular drug therapies in various cancers. Despite the fact that cell-ECM interactions are involved in processes of nuclear homeodynamics such as gene expression and DNA repair, it remains to be unraveled which integrins specifically co-control gene expression and accessibility and how. Our own preliminary data demonstrate that the α7 integrin subunit, which together with the β1 integrin subunit forms an important laminin-binding receptor, is overexpressed in many cancers, including HNSCC. In HNSCC cells, α7 integrin inhibition shows both radiochemosensitizing potential and significant changes in histone post-translational modifications. This led us to hypothesize that α7 integrin exerts an essential regulatory function on gene accessibility and expression. The aim of this study is to systematically characterize α7 integrin-dependent regulation of (i) gene expression, (ii) genome-wide, site-specific changes in gene accessibility, and (iii) survival/proliferation processes (including clonogenic survival, cell death, cell cycling, DNA repair) upon different types of genotoxic stress in a series of human HNSCC cell models. To ensure more physiological growth conditions, cell models are cultured in a three-dimensional matrix. In combination with extensive bioinformatic analyses of RNA and ATAC sequencing datasets, wet-lab experiments are performed to uncover the functional consequences of α7 integrin silencing-induced changes in gene expression and chromatin organization on cell survival and resistance to genotoxic stress as induced by X-ray irradiation and various conventional chemotherapeutic agents. We anticipate that our in vitro approach will provide initial insights and a better functional understanding of how cell-ECM interactions (here α7 integrin-related), which are often disrupted in cancer, co-regulate critical nuclear events in terms of stress response and resistance to routinely applied clinical therapies.

头颈鳞状细胞癌（HNSCC）是一种需求未得到满足的癌症。尽管付出了巨大努力来优化治疗，但在过去三十年中，局部控制和总体生存率仍然保持稳定。多种遗传、表观遗传和微环境因素从根本上影响 HNSCC 对治疗的反应。耐药性的一个关键决定因素是整合素介导的细胞-细胞外基质（ECM）相互作用，其破坏已被证明会引起对各种癌症的放疗、化疗或分子药物治疗的敏感性。尽管细胞-ECM 相互作用涉及核稳态动力学过程，例如基因表达和 DNA 修复，但哪些整合素特异性地共同控制基因表达和可及性以及如何共同控制仍有待阐明。我们自己的初步数据表明，α7 整合素亚基与 β1 整合素亚基一起形成重要的层粘连蛋白结合受体，在包括 HNSCC 在内的许多癌症中过度表达。在 HNSCC 细胞中，α7 整合素抑制显示出放射化学增敏潜力和组蛋白翻译后修饰的显着变化。这使我们假设 α7 整合素对基因可及性和表达发挥重要的调节功能。本研究的目的是系统地表征在一系列人类 HNSCC 细胞模型中不同类型的基因毒性应激下，α7 整合素依赖性调节（i）基因表达，（ii）基因组范围内基因可及性的位点特异性变化，以及（iii）生存/增殖过程（包括克隆形成生存、细胞死亡、细胞周期、DNA 修复）。为了保证更多的生理生长条件，细胞模型在三维矩阵中培养。结合 RNA 和 ATAC 测序数据集的广泛生物信息学分析，进行湿实验室实验，以揭示 α7 整合素沉默诱导的基因表达和染色质组织变化对细胞存活和对 X 射线照射和各种常规化疗药物诱导的基因毒性应激的抵抗力的功能影响。我们预计，我们的体外方法将为细胞-ECM相互作用（此处为α7整合素相关）如何在应激反应和对常规临床治疗的抵抗方面共同调节关键核事件提供初步见解和更好的功能理解，这种相互作用在癌症中经常被破坏。