YAP1 activation by human papillomavirus E7 promotes basal cell identity in squamous epithelia
- University of Pennsylvania, United States
- Aurora St. Luke's Medical Center, United States
Abstract
Persistent human papillomavirus (HPV) infection of stratified squamous epithelial cells causes nearly five percent of cancer cases worldwide. HPV-positive oropharyngeal cancers harbor few mutations in the Hippo signaling pathway compared to HPV-negative cancers at the same anatomical site, prompting the hypothesis that an HPV-encoded protein inactivates the Hippo pathway and activates the Hippo effector YAP1. The HPV E7 oncoprotein is required for HPV infection and for HPV-mediated oncogenic transformation. We investigated the effects of HPV oncoproteins on YAP1 and found that E7 activates YAP1, promoting YAP1 nuclear localization in basal epithelial cells. YAP1 activation by HPV E7 required that E7 bind and degrade the tumor suppressor PTPN14. E7 required YAP1 transcriptional activity to extend the lifespan of primary keratinocytes, indicating that YAP1 activation contributes to E7 carcinogenic activity. Maintaining infection in basal cells is critical for HPV persistence, and here we demonstrate that YAP1 activation causes HPV E7 expressing cells to be retained in the basal compartment of stratified epithelia. We propose that YAP1 activation resulting from PTPN14 inactivation is an essential, targetable activity of the HPV E7 oncoprotein relevant to HPV infection and carcinogenesis.
Data availability
Original, uncropped Western blot images are contained in Figure 4B - Source Data 1, Figure 4 supplement 1 - Source Data 1, Figure 7 supplement 1D - Source Data 1, Figure 7 supplement 1F - Source Data 1
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Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortalhttps://www.cbioportal.org/.
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Analysis of gene expression in primary human foreskin keratinocytes +/- HPV16 E7 or PTPN14 knockoutNCBI Gene Expression Omnibus, GSE121906.
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Analysis of gene expression in primary human foreskin keratinocytes (HFK) +/- HPV18 E7NCBI Gene Expression Omnibus, GSE150201.
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Human neonatal foreskin epidermisNCBI Gene Expression Omnibus, GSE147482.
Article and author information
Author details
Joshua Hatterschide
Funding
National Institute of Allergy and Infectious Diseases (T32 AI007324)
- Joshua Hatterschide
National Institute of Dental and Craniofacial Research (F31 DE030365)
- Joshua Hatterschide
American Cancer Society (131661-RSG-18-048-01-MPC)
- Joshua Hatterschide
- Paola Castagnino
- Hee Won Kim
- Elizabeth A White
National Institute of Allergy and Infectious Diseases (R01 AI148431)
- Joshua Hatterschide
- Paola Castagnino
- Hee Won Kim
- Elizabeth A White
National Institute of Dental and Craniofacial Research (R01 DE027185)
- Devraj Basu
National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30 AR068589)
- Elizabeth A White
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The University of Pennsylvania Skin Biology and Diseases Resource-based Center (SBDRC) was supported by NIH grant P30 AR068589
Ethics
Human subjects: All patient-derived materials and clinical data in this study were obtained from patients who underwent surgery to remove an oral cavity or oropharyngeal cancer. Patients were counseled preoperatively and provided informed consent under University of Pennsylvania IRB-approved protocol #417200 "Head and Neck Cancer Specimen Bank" (PI: D. Basu) by signing a combined informed consent and HIPAA form for use of tissue for research. Consent under this longstanding and currently active protocol explicitly provides permission to access surgically removed fresh tumor tissue that is not needed for pathologic analysis as well as to access FFPE tumor tissue in the pathology archive at a later date. It also provides explicit permission to publish deidentified analyses of these resources. Patient care is not altered under this protocol, which carries minimal risk. Minors and other vulnerable populations are not included in the study.
Copyright
© 2022, Hatterschide et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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YAP1 activation by human papillomavirus E7 promotes basal cell identity in squamous epithelia
eLife 11:e75466.
https://doi.org/10.7554/eLife.75466
Further reading
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- Cancer Biology
Background:
Cervical adenocarcinoma (ADC) is more aggressive compared to other types of cervical cancer (CC), such as squamous cell carcinoma (SCC). The tumor immune microenvironment (TIME) and tumor heterogeneity are recognized as pivotal factors in cancer progression and therapy. However, the disparities in TIME and heterogeneity between ADC and SCC are poorly understood.
Methods:
We performed single-cell RNA sequencing on 11 samples of ADC tumor tissues, with other 4 SCC samples served as controls. The immunochemistry and multiplexed immunofluorescence were conducted to validate our findings.
Results:
Compared to SCC, ADC exhibited unique enrichments in several sub-clusters of epithelial cells with elevated stemness and hyper-malignant features, including the Epi_10_CYSTM1 cluster. ADC displayed a highly immunosuppressive environment characterized by the enrichment of regulatory T cells (Tregs) and tumor-promoting neutrophils. The Epi_10_CYSTM1 cluster recruits Tregs via ALCAM-CD6 signaling, while Tregs reciprocally induce stemness in the Epi_10_CYSTM1 cluster through TGFβ signaling. Importantly, our study revealed that the Epi_10_CYSTM1 cluster could serve as a valuable predictor of lymph node metastasis for CC patients.
Conclusions:
This study highlights the significance of ADC-specific cell clusters in establishing a highly immunosuppressive microenvironment, ultimately contributing to the heightened aggressiveness and poorer prognosis of ADC compared to SCC.
Funding:
Funded by the National Natural Science Foundation of China (82002753; 82072882; 81500475) and the Natural Science Foundation of Hunan Province (2021JJ40324; 2022JJ70103).
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- Cancer Biology
- Immunology and Inflammation
In this study, we present a proof-of-concept classical vaccination experiment that validates the in silico identification of tumor neoantigens (TNAs) using a machine learning-based platform called NAP-CNB. Unlike other TNA predictors, NAP-CNB leverages RNA-seq data to consider the relative expression of neoantigens in tumors. Our experiments show the efficacy of NAP-CNB. Predicted TNAs elicited potent antitumor responses in mice following classical vaccination protocols. Notably, optimal antitumor activity was observed when targeting the antigen with higher expression in the tumor, which was not the most immunogenic. Additionally, the vaccination combining different neoantigens resulted in vastly improved responses compared to each one individually, showing the worth of multiantigen-based approaches. These findings validate NAP-CNB as an innovative TNA identification platform and make a substantial contribution to advancing the next generation of personalized immunotherapies.
