Establishment of a Plasticity-Associated Risk Model Based on a SOX2- and SOX9-Related Gene Set in Head and Neck Squamous Cell Carcinoma

Abstract

Recent studies highlighted SOX2 and SOX9 as key determinants for cancer-cell plasticity and demonstrated that cisplatin-induced adaptation in oral squamous cell carcinoma (SCC) is acquired by an inverse regulation of both transcription factors. However, the association between SOX2/SOX9-related genetic programs with risk factors and genetic or epigenetic alterations in primary head and neck SCC (HNSCC), and their prognostic value is largely unknown. Here, we identified differentially-expressed genes (DEG) related to SOX2 and SOX9 transcription in The Cancer Genome Atlas (TCGA)-HNSC, which enable clustering of patients into groups with distinct clinical features and survival. 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. Differences in the mutational landscape among risk groups of TCGA-HNSC demonstrated an enrichment of truncating NSD1 mutations for the low-risk group and elucidated DNA methylation as modulator of SOX2 expression. Gene set variation analysis (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. Implications: The established risk model identifies patients with primary HNSCC, but also other cancers at a higher risk for treatment failure, who might benefit from a therapy targeting SOX2/SOX9-related gene regulatory and signaling networks.

The Role of SOX2 and SOX9 in Radioresistance and Tumor Recurrence

“…As a result of this plasticity, cancer cells can reprogram their gene expression in response to tumor development and therapeutic resistance [40]. Indeed, multiple studies have suggested an inverse correlation between the expression of SOX2 and SOX9 in cancer in a context dependent manner [25,41,42]. Here, in IHC staining analysis of the HIPO-HNC cohort we observed that gain or loss of expression depends on the region of the tumor.…”

“…Sharma et al, demonstrated that a drug-induced adaptation was acquired upon loss of SOX2 with a concomitant gain in SOX9 in tumor cells [43]. Khorani et al, using DEGs gene related to SOX2 and SOX9, established an in silico prognostic risk model which suggests that inverse expression of both TFs may modulate cellular plasticity [41]. Thus, it may be that the tumor cells need a certain balance of expression to be able to migrate and/or resist treatment, suggesting a possible regulatory relationship between these two genes in HNSCC.…”

SOX9 promotes stemness in the CAL27 cell line of tongue squamous cell carcinoma

“…Longitudinal single‐cell RNA sequencing 38 revealed that the development of drug resistance and drug‐induced tumor adaptation in oral squamous cell carcinoma under cisplatin selective pressure was accompanied by an increase in SOX9 expression. This suggests that treatment‐induced cellular plasticity is strongly correlated with SOX9 expression, which was also confirmed in head and neck squamous carcinoma 39 . Moreover, due to the development of acquired resistance, platinum‐based treatments for metastatic non‐small cell lung cancer often fail.…”

“…This suggests that treatment-induced cellular plasticity is strongly correlated with SOX9 expression, which was also confirmed in head and neck squamous carcinoma. 39 In conclusion, given that SOX9 is a promising CSC target, it appears that creating innovative drugs for tumor-targeted therapy is a viable treatment option.…”

ABCG2, CD44 and SOX9 are increased with the acquisition of drug resistance and involved in cancer stem cell activities in head and neck squamous cell carcinoma cells

“…Studies showed that SOX9 is mutated in skeletal malformations, XY transsexuals, and campomelic dysplasia characterized by neonatal lethality ( 36 ), and SOX9 is important for the differentiation of embryonic stem cells into salivary glands ( 37 ). Furthermore, SOX9 is associated with prognosis in lung cancer and breast cancer and a risk factor for chemotherapy failure in head and neck cancer ( 38 , 39 ). Our study revealed that SOX9 is involved in drug excretion and cell invasion in R HSC-3 cells.…”