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Abstract

Background: Cancer cell plasticity is a fundamental process in the generation of tumor heterogeneity (1). Clonal selection and enrichment of drug-resistant cancer cells are the most common drivers of treatment failure. Identifying underlying molecular principles of tumor heterogeneity remains a major challenge (2). Recently, several studies demonstrated cancer cell plasticity in the pathogenesis and therapy of head and neck cancer. They highlighted SOX2 and SOX9 as key determinants for intrinsic cancer cell plasticity and demonstrated that cisplatin-induced adaptation in oral squamous cell carcinoma is acquired by an inverse regulation of both transcription factors. However, the association between SOX2/SOX9-related gene regulatory networks with risk factors and genetic or epigenetic alterations in primary head and neck squamous cell carcinoma (HNSCC), and their prognostic value is largely unknown. In the first part of my research project, I identified differentially expressed genes (DEGs) related to inverse SOX2 and SOX9 transcription in TCGA-HNSC, which enabled the clustering of patients into groups with distinct clinical features and survival (3). In the second part, I investigate the cancer-neuron interaction (CNI) as a potential mode of extrinsic regulation of cancer cell plasticity. Early in cancer development, nerve fibers (NF) form and infiltrate tumor tissue, and the density of NF in solid tumors has been associated with a poor prognosis. Though the origin of cancer-related NF and the mode of their mutual interaction with cancer or stromal cells of the tumor microenvironment (TME) are elusive. NF and their associated cells such as Schwann cells (SCs) are emerging as key regulators of cancer initiation, progression, and metastasis. Therefore, SCs might serve as a surrogate marker for the extent of CNI. SCs interact with cancer cells, and the accompanying process of axonal sprouting at the premalignant phase provides the first cancer access to nerves, leading to neural dissemination at an early disease stage (4,5). So, as its crucial role in attracting cancer cells to the perineural niche and enabling adhesion of cancer cells to the nerves, their roles need to be generously addressed in the cancer-nerve cross talk in all solid tumors, including HNSCC. Aims: Various tumor cell-intrinsic and extrinsic factors have been demonstrated to be involved in regulating lineage plasticity. The mechanism of the tumor cell-intrinsic lineage plasticity (e.g., mutational landscape, epigenetic regulation, signaling, and gene regulatory networks), while tumor cell-extrinsic lineage plasticity depends on (e.g., cellular and matrix components of TME). So, in this study, I aimed extensively to examine cancer cell plasticity in the pathogenesis and therapy of HNSCC and other tumors. 1. Focus on cancer cell-intrinsic mechanisms and modulators of plasticity, particularly the role of SOX family members in cancer lineage plasticity, and more precisely the inverse regulation of SOX2- and SOX9-related gene networks in HNSCC and other tumor entities. Clinical relevance of inverse SOX2-SOX9 expression for HNSCC and other tumor entities. Establishment risk models to identify patients with primary HNSCC and other cancers at a higher risk for treatment failure, who might benefit from a therapy targeting SOX2/SOX9-related gene regulatory and signaling networks. Molecular and cellular characterization of the predicted risk models in HNSCC and other tumor entities. 2. Focus on cancer cell-extrinsic mechanisms and modulators of plasticity, particularly the role of molecular mechanisms contributing to the complex crosstalk between cancer cells, neurons, and their associated glial cells such as Schwann cells. Clinical relevance of nerve fibers and associated cells such as Schwann cells for HNSCC and other tumor entities. Molecular characterization of cancer-nerve crosstalk in HNSCC and other tumor types. Establishment and analysis of pre-clinical models as a proof-of-concept for new therapeutic strategies. Results: 1. Differentially expressed genes (DEG) related to SOX2 and SOX9 transcription were identified in TCGA-HNSC, which enables the clustering of patients into groups with distinct clinical features and survival. Moreover, a prognostic risk model was established by LASSO Cox regression based on expression patterns of DEGs in TCGA-HNSC (training cohort) and was confirmed in independent HNSCC validation cohorts as well as other cancer cohorts from TCGA. Additionally, differences in the mutational landscape among risk groups of TCGA-HNSC demonstrated enrichment of truncating NSD1 mutations for the low-risk group and elucidated DNA methylation as a modulator of SOX2 expression. The GSVA revealed differences in several oncogenic pathways among risk groups, including upregulation of gene sets related to oncogenic KRAS signaling for the high-risk group. Finally, in silico drug screen analysis revealed numerous compounds targeting EGFR signaling with significantly lower efficacy for cancer cell lines with a higher risk phenotype, but also indicated potential vulnerabilities. 2. A SC-related 43-gene set was elucidated as an accurate surrogate for the presence of peripheral nerves across solid tumor entities. This model is characterized by higher oncogenic pathway activities such as TGF-β signaling in the group with a high SC score with an immunosuppressive phenotype and higher PI3K-AKT-MTOR pathway and cell cycle pathway activity in the group with a lower SC score with an immune active phenotype and more sensitivity to topoisomerase agents as potential treatment vulnerabilities. Finally, the impact of PI3K pathway activity on TME abundance of peripheral neurons is context-dependent and dominated by the TP53 status. References: 1. DOI: 10.1038/nrc3261 2. DOI: 10.1016/j.cell.2017.01.018 3. DOI: 10.1158/1541-7786.MCR-21-0066 4. DOI: 10.1038/nrc.2016.38 5. DOI: 10.1016/0016-5085(94)90080-9