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

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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.