Barriers to generating PDX models of HPV‐related head and neck cancer

Abstract

Objectives/Hypothesis Delineate factors impacting creation and use of patient-derived xenografts (PDXs) of human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs). Study Design Laboratory-based translational study. Methods 51 surgically resected HNSCCs, including 31 HPV+ cancers, were implanted into NOD/SCID/IL-2Rγ−/− (NSG) mice using standardized methodology. Clinical and pathologic factors were tested for association with engraftment. The gross, histologic, and molecular features of established HPV+ PDXs were analyzed in comparison to their tumors of origin. Results Negative HPV status and perineural invasion (PNI) were independent, additive factors associated with increased PDX formation. Epstein-Barr Virus-positive (EBV+) human large B-cell lymphomas grew from 32% of HPV+ HNSCC cases that failed to engraft. Successfully established HPV+ PDXs retained basaloid histology and often developed cystic growth patterns typical of HPV+ nodal metastases. They also maintained elevated p16INK4A levels and expression of E6/E7 viral oncogene transcripts. Conclusion Reduced engraftment by HPV+ tumors lacking PNI likely results in selection biases in HNSCC PDX models. Formation of EBV+ lymphomas in NSG mice further reduces generation of HPV+ models and must be ruled out before long-term use of PDXs. Nevertheless, retention of distinctive pathologic traits and viral oncogene expression by HPV+ PDXs provides a viable in vivo platform for basic and translational studies as well as a resource for generating advanced in vitro models.

Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer

“…Additionally, PDXs from HPV-negative tumors tended to show a higher engraftment rate compared with those from HPV-positive tumors. These results of our study are consistent with prior reports [13].…”

“…Several groups have established PDX models of HNSCC, characterized their genomic fidelity and therapeutic response profiles [10][11][12][13][14][15]. Herein, we established PDXs using surgically resected or biopsied tumor tissues from HNSCC patients and characterized both histological and genomic fidelities of the established PDXs.…”

Integrated Analysis of Whole-Genome ChIP-Seq and RNA-Seq Data of Primary Head and Neck Tumor Samples Associates HPV Integration Sites with Open Chromatin Marks

“…In addition to being small, HPV+ HNSCC tumors are often not surgically excised, limiting primary tissue availability. In fact, there are fewer than 10 HPV+ HNSCC cell lines worldwide (10), and a limited number of HPV+ HNSCC PDXs are currently described (39). These limitations are reflected in relatively small cohorts of HPV+ HNSCC samples in large consortia for HNSCC genomics profiling, such as TCGA (3).…”

Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models

“…Despite overall fidelity of HNSCC PDXs to the genetic landscape of HPV+ tumors, low engraftment rates in immunodeficient mice (13) predicted molecular selection biases in the PDXs. To evaluate for such effects that might provide models for more aggressive tumor subtypes, mutations in CGC genes that occurred in at least two HPV+ PDXs were compared in frequency to their counterparts in TCGA (Figure 2A).…”