Therapeutic implications of transcriptomics in head and neck cancer patient-derived xenografts

被引:3
|
作者
Lee, Rex H. [1 ]
Roy, Ritu [2 ]
Li, Hua [1 ]
Hechmer, Aaron [2 ]
Zhu, Tian Ran [1 ]
Izgutdina, Adila [1 ]
Olshen, Adam B. [2 ,3 ]
Johnson, Daniel E. [1 ]
Grandis, Jennifer R. [1 ]
机构
[1] Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA
[3] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA
来源
PLOS ONE | 2023年 / 18卷 / 03期
基金
美国国家卫生研究院;
关键词
HUMAN-PAPILLOMAVIRUS; REPAIR; HPV;
D O I
10.1371/journal.pone.0282177
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:18
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