1. Context-Dependent Regulation of Peripheral Nerve Abundance by the PI3K Pathway in the Tumor Microenvironment of Head and Neck Squamous Cell Carcinoma.
- Author
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Khorani K, Burkart S, Weusthof C, Han R, Liang S, Stögbauer F, and Hess J
- Subjects
- Humans, Peripheral Nerves pathology, Peripheral Nerves metabolism, Peripheral Nerves virology, Head and Neck Neoplasms virology, Head and Neck Neoplasms pathology, Head and Neck Neoplasms genetics, Head and Neck Neoplasms metabolism, Mutation genetics, TOR Serine-Threonine Kinases metabolism, Class I Phosphatidylinositol 3-Kinases metabolism, Class I Phosphatidylinositol 3-Kinases genetics, Schwann Cells metabolism, Schwann Cells pathology, Schwann Cells virology, PTEN Phosphohydrolase metabolism, PTEN Phosphohydrolase genetics, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Tumor Microenvironment, Squamous Cell Carcinoma of Head and Neck pathology, Squamous Cell Carcinoma of Head and Neck virology, Squamous Cell Carcinoma of Head and Neck genetics, Squamous Cell Carcinoma of Head and Neck metabolism, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction
- Abstract
Recent studies have highlighted neurons and their associated Schwann cells (SCs) as key regulators of cancer development. However, the mode of their interaction with tumor cells or other components of the tumor microenvironment (TME) remains elusive. We established an SC-related 43-gene set as a surrogate for peripheral nerves in the TME. Head and neck squamous cell carcinoma (HNSCC) from The Cancer Genome Atlas (TCGA) were classified into low, intermediate and high SC score groups based on the expression of this gene set. Perineural invasion (PNI) and TGF-β signaling were hallmarks of SC
high tumors, whereas SClow tumors were enriched for HPV16-positive OPSCC and higher PI3K-MTOR activity. The latter activity was partially explained by a higher frequency of PTEN mutation and PIK3CA copy number gain. The inverse association between PI3K-MTOR activity and peripheral nerve abundance was context-dependent and influenced by the TP53 mutation status. An in silico drug screening approach highlighted the potential vulnerabilities of HNSCC with variable SC scores and predicted a higher sensitivity of SClow tumors to DNA topoisomerase inhibitors. In conclusion, we have established a tool for assessing peripheral nerve abundance in the TME and provided new clinical and biological insights into their regulation. This knowledge may pave the way for new therapeutic strategies and impart proof of concept in appropriate preclinical models.- Published
- 2024
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