Comprehensive Characterization of Stem Cell Landscape Identifies Novel Stemness-Relevant Genes for Nasopharyngeal Carcinoma Therapy

TL;DR

This study identifies new genes linked to cancer stem cells in nasopharyngeal carcinoma, offering potential targets for treating aggressive or recurring tumors.

Contribution

The study discovers novel stemness-related genes (PSMC3IP, NABP2, CDC45, HJURP) for nasopharyngeal carcinoma therapy.

Findings

NPC patients were classified into two subtypes with distinct stemness features, prognosis, and immune profiles.

PSMC3IP, NABP2, CDC45, and HJURP were validated as stemness-related genes promoting cancer stem cell properties.

These genes are associated with the effectiveness of telomerase inhibitors in NPC treatment.

Abstract

Nasopharyngeal carcinoma (NPC) is a rare type of head and neck malignant tumor with specific geographical distribution. Growing evidence reveals the dominant roles of cancer stem cells (CSCs) in tumor progression and therapy resistance. However, the heterogeneity of CSCs and potential stemness-related markers for NPC patients are still largely unknown. We undertook a systematical analysis, dissecting the stemness heterogeneity of NPC patients. We classified NPC patients into two optimal clusters based on stemness-related gene lists, which were characterized by distinct clinical outcomes, immune phenotypes, and drug response. The immune cell exclusion is associated with the presence of the NPC stem cell-like phenotype. In particular, novel stemness-related markers including PSMC3IP, NABP2, CDC45, and HJURP were prioritized via WGCNA and Cox regression analysis. Moreover, their stemness traits in NPC cells were verified by Western blot, sphere formation, and CCK8 assays. Our results will provide valuable targets against metastatic or recurrent NPC.

Background: Metastasis and recurrence account for the failure of nasopharyngeal carcinoma (NPC) treatment. Growing evidence indicates the dominant roles of cancer stem cells (CSCs) in tumor progression and therapy resistance. However, the heterogeneity of CSCs and potential stemness-related markers in NPC patients are still largely unknown. Methods: Consensus clustering was first applied to identify robust stemness subtypes for NPC patients based on the activities of stem cell gene sets. The differences in clinical outcomes, tumor immune microenvironment (TIME), and drug response were compared between subtypes. The stemness-related markers were prioritized via weighted gene correlation network analysis (WGCNA) and Cox regression, and verified through in vitro experiments. Results: NPC patients were classified into C1 and C2 subtypes. The C2 subtype exhibited higher activities of stem cell gene sets, worse prognosis, and aggressive tumor progression thus defined as stem cell-like tumor phenotype. The exclusionary relationships between tumor stemness and TIME infiltration were observed. The efficacy of several drugs and immunotherapy varied between NPC stemness subtypes. Through the WGCNA and survival analysis, we found that PSMC3IP, NABP2, CDC45, and HJURP were stemness-relevant genes. Sphere formation assays and analysis of the protein expression of stem cell markers by Western blotting revealed the roles of PSMC3IP, NABP2, CDC45, and HJURP in promoting CSC properties. Moreover, these genes were found to be related to the therapeutic effect of telomerase inhibitor in CCK8 experiments. Conclusions: This study systematically characterized two NPC subtypes with distinct stemness features, clinical outcomes, and TIME features. Novel stemness-related markers will provide valuable targets against metastatic or recurrent NPC.

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