Journal Article

Loss of p53-DREAM-mediated repression of cell cycle genes as a driver of lymph node metastasis in head and neck cancer

Gevaert, Olivier, Gentles, Andrew J., Espín-Pérez, Almudena, Saumyaa, Saumyaa, Bedi, Nikita, Plevritis, Sylvia K., Brennan, Kevin, Chang, Serena, Shin, June Ho, Sunwoo, John B.

2023

Overview

Background The prognosis for patients with head and neck cancer (HNC) is poor and has improved little in recent decades, partially due to lack of therapeutic options. To identify effective therapeutic targets, we sought to identify molecular pathways that drive metastasis and HNC progression, through large-scale systematic analyses of transcriptomic data. Methods We performed meta-analysis across 29 gene expression studies including 2074 primary HNC biopsies to identify genes and transcriptional pathways associated with survival and lymph node metastasis (LNM). To understand the biological roles of these genes in HNC, we identified their associated cancer pathways, as well as the cell types that express them within HNC tumor microenvironments, by integrating single-cell RNA-seq and bulk RNA-seq from sorted cell populations. Results Patient survival-associated genes were heterogenous and included drivers of diverse tumor biological processes: these included tumor-intrinsic processes such as epithelial dedifferentiation and epithelial to mesenchymal transition, as well as tumor microenvironmental factors such as T cell-mediated immunity and cancer-associated fibroblast activity. Unexpectedly, LNM-associated genes were almost universally associated with epithelial dedifferentiation within malignant cells. Genes negatively associated with LNM consisted of regulators of squamous epithelial differentiation that are expressed within well-differentiated malignant cells, while those positively associated with LNM represented cell cycle regulators that are normally repressed by the p53-DREAM pathway. These pro-LNM genes are overexpressed in proliferating malignant cells of TP53 mutated and HPV + ve HNCs and are strongly associated with stemness, suggesting that they represent markers of pre-metastatic cancer stem-like cells. LNM-associated genes are deregulated in high-grade oral precancerous lesions, and deregulated further in primary HNCs with advancing tumor grade and deregulated further still in lymph node metastases. Conclusions In HNC, patient survival is affected by multiple biological processes and is strongly influenced by the tumor immune and stromal microenvironments. In contrast, LNM appears to be driven primarily by malignant cell plasticity, characterized by epithelial dedifferentiation coupled with EMT-independent proliferation and stemness. Our findings postulate that LNM is initially caused by loss of p53-DREAM-mediated repression of cell cycle genes during early tumorigenesis.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Annotations / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Biopsy / Cancer / Cancer Research / Care and treatment / Cell cycle / Cell differentiation / Cell survival / Cell-mediated immunity / Clinical outcomes / Datasets / Development and progression / Epithelial-Mesenchymal Transition - genetics / Gene expression / Gene silencing / Genes / Genes, cdc / Genetic aspects / Genetic transcription / Head & neck cancer / Head and neck cancer / Head and Neck Neoplasms - genetics / Health aspects / Human Genetics / Human papillomavirus / Humans / Lymph node metastasis / Lymph nodes / Lymphatic Metastasis / Lymphatic system / Lymphocytes T / Medical prognosis / Medicine/Public Health / Meta-analysis / Metabolomics / Metadata / Metastases / Metastasis / Missing data / Mutation / p53 Protein / p53-DREAM pathway / Papillomavirus infections / Patients / Prognosis / RNA / RNA sequencing / Single-cell RNA-Seq / Standard scores / Stem cells / Systems Biology / T cells / Therapeutic targets / Transcriptomics / Tumor microenvironment / Tumor Microenvironment - genetics / Tumor proteins / Tumor Suppressor Protein p53 - genetics / Tumorigenesis / Tumors