Nicole D Facompre1, Varun Sahu1, Kathleen T Montone1,2, Kayla M Harmeyer1, Hiroshi Nakagawa3, Anil K Rustgi3, Gregory S Weinstein1, Phyllis A Gimotty4, Devraj Basu1,5,6. 1. Department of Otorhinolaryngology-Head and Neck Surgery, The University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. 2. Department of Pathology, The University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. 3. Department of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. 4. Department of Biostatistics and Epidemiology , The University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. 5. Philadelphia VA Medical Center, Philadelphia, Pennsylvania, U.S.A. 6. Wistar Institute, Philadelphia, Pennsylvania, U.S.A.
Abstract
OBJECTIVES/HYPOTHESIS: Delineate factors impacting the 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: Fifty-one 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 the generation of HPV + models and must be ruled out before long-term use of PDXs. Nevertheless, the 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. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2777-2783, 2017.
OBJECTIVES/HYPOTHESIS: Delineate factors impacting the 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: Fifty-one 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 the generation of HPV + models and must be ruled out before long-term use of PDXs. Nevertheless, the 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. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2777-2783, 2017.
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