Therapeutic implications of transcriptomics in head and neck cancer patient-derived xenografts
Rex H Lee1, Ritu Roy2, Hua Li1
1Department of Otolaryngology, Head and Neck Surgery, University of California, San Francisco, San Francisco, California, United States of America.
Abstract:
There are currently no clinical strategies utilizing tumor gene expression to inform therapeutic selection for patients with head and neck squamous cell carcinoma (HNSCC). One of the challenges in developing predictive biomarkers is the limited characterization of preclinical HNSCC models. Patient-derived xenografts (PDXs) are increasingly recognized as translationally relevant preclinical avatars for human tumors; however, the overall transcriptomic concordance of HNSCC PDXs with primary human HNSCC is understudied, especially in human papillomavirus-associated (HPV+) disease. Here, we characterized 64 HNSCC PDXs (16 HPV+ and 48 HPV-) at the transcriptomic level using RNA-sequencing. The range of human-specific reads per PDX varied from 64.6%-96.5%, with a comparison of the most differentially expressed genes before and after removal of mouse transcripts revealing no significant benefit to filtering out mouse mRNA reads in this cohort. We demonstrate that four previously established HNSCC molecular subtypes found in The Cancer Genome Atlas (TCGA) are also clearly recapitulated in HNSCC PDXs. Unsupervised hierarchical clustering yielded a striking natural division of HNSCC PDXs by HPV status, with C19orf57 (BRME1), a gene previously correlated with positive response to cisplatin in cervical cancer, among the most significantly differentially expressed genes between HPV+ and HPV- PDXs. In vivo experiments demonstrated a possible relationship between increased C19orf57 expression and superior anti-tumor responses of PDXs to cisplatin, which should be investigated further. These findings highlight the value of PDXs as models for HPV+ and HPV- HNSCC, providing a resource for future discovery of predictive biomarkers to guide treatment selection in HNSCC.
Insights
Patient-derived xenografts (PDXs) accurately model head and neck squamous cell carcinoma (HNSCC) subtypes, including HPV+ disease. Gene expression in PDXs shows potential for predicting cisplatin response, aiding future HNSCC treatment selection.
Area of Science:
- Oncology
- Genomics
- Translational Research
Background:
- Limited clinical strategies exist for using tumor gene expression to guide head and neck squamous cell carcinoma (HNSCC) therapy.
- Preclinical models for HNSCC lack comprehensive characterization, hindering predictive biomarker development.
- Patient-derived xenografts (PDXs) are valuable preclinical models, but their transcriptomic similarity to human HNSCC, especially HPV-associated types, needs further study.
Purpose of the Study:
- To assess the transcriptomic concordance of HNSCC patient-derived xenografts (PDXs) with primary human tumors.
- To evaluate the utility of HNSCC PDXs in recapitulating known molecular subtypes and reflecting HPV status.
- To identify potential gene expression biomarkers for therapeutic selection in HNSCC.
Main Methods:
- RNA-sequencing was performed on 64 HNSCC PDXs (16 HPV+ and 48 HPV-).
- Transcriptomic data was analyzed for human-specific reads and compared with and without mouse transcript filtering.
- Unsupervised hierarchical clustering was used to analyze molecular subtypes and HPV status.
- Gene expression differences between HPV+ and HPV- PDXs were investigated, including C19orf57 (BRME1).
Main Results:
- HNSCC PDXs successfully recapitulated four established molecular subtypes found in The Cancer Genome Atlas (TCGA).
- A clear separation of PDXs based on HPV status was observed through unsupervised clustering.
- C19orf57 (BRME1) was significantly differentially expressed between HPV+ and HPV- PDXs.
- In vivo studies suggested a correlation between higher C19orf57 expression and improved anti-tumor response to cisplatin.
Conclusions:
- HNSCC PDXs are valuable translational models for both HPV+ and HPV- disease.
- These PDXs can serve as a resource for discovering predictive biomarkers to guide HNSCC treatment.
- Further investigation into C19orf57's role in cisplatin response is warranted for potential clinical application.
