Study Provides a Comprehensive Picture of the Connections Between the HPV Virus and Head and Neck Cancer

The human papilloma virus (HPV) is widely known to cause almost all cases of cervical cancer. However, you might not know that HPV also causes 70% of oropharyngeal cancers, a subgroup of head and neck cancers that affect the mouth, tongue, and tonsils. Although vaccines that protect against HPV infection are now available, they are not yet widespread, especially in men, and also do not treat the large number of currently infected cancer patients.

Patients with head and neck cancer caused by HPV respond very differently to treatments than those whose cancer is associated with the consumption of tobacco products. The first group generally has better results, with nearly 80% of patients surviving more than 5 years after diagnosis, compared with only 45 to 50% of patients with tobacco-related cancers.

To better understand what might be causing these differences, a team of scientists led by Nevan J. Krogan, PhD, principal investigator at the Gladstone Institutes, takes a unique approach focusing on the carcinogenic virus. They have recently mapped the interactions between all HPV proteins and human proteins for the first time. Their findings are published today in the journal Discovery of cancer.

"With our study, we identified several new protein interactions that were not known to cause cancer, thereby expanding our knowledge of the oncogenic roles of the HPV virus," said Krogan, professor of cellular and molecular pharmacology at UC San Francisco (UCSF) and the director of Quantitative Biosciences Institute (QBI) at UCSF. "The human proteins we found in interaction with HPV are involved in virus and tobacco-related cancers, which means that they could be potential targets for the development of new drugs or therapies."

A complete picture of the virus-cancer connections

Krogan and Manon Eckhardt, PhD, a postdoctoral researcher in his Gladstone lab, have developed an integrated strategy to identify all the interactions between HPV proteins and human proteins. First, using a method called mass spectrometry, they discovered a total of 137 interactions between HPV and human proteins.

Then, in collaboration with biologist Wei Zhang, Ph.D., at the laboratory of Trey Ideker, Ph.D., at the University of San Diego School of Medicine, they examined entire networks of each protein – rather as individual proteins – to detect the most important players. They also compared their protein list with data from HPV-associated cancer samples published by the Atlas of the Cancer Genome project. This large consortium has cataloged genetic mutations in tumors of various cancers.

"We have integrated these two datasets to gain a complete overview of potential carcinogenic interactions between HPV and head and neck cancers," said Dr. Krogan, co-director of the Cancer Cell Mapping Initiative. . "This combined proteomic and genetic approach has provided us with a systematic way to study the cellular mechanisms diverted by virus-induced cancers."

Common pathways in HPV-induced cancers and smokers

By superimposing protein interaction and genomic data, scientists have discovered that the HPV virus targets the same human proteins that are frequently mutated in smoking-related cancers. Interestingly, these proteins are not mutated in HPV-positive cancers.

For example, their results confirmed a well-established interaction between the human p53 protein and an HPV protein called E6. In HPV-negative (smoking-related) cancers, p53 is mutated in almost all cases. However, the same protein is rarely mutated in HPV-positive cancer patients.

"In either case, when p53 is inactivated, it leads to cancer," said Eckhardt, one of the first authors of the paper. "The difference is that the HPV virus finds a different way to attack the same protein."

In smoking-related cancers, p53 is mutated, which causes cancer. Instead, in HPV-positive cancers, the E6 viral protein interacts with p53 and inactivates it, causing the same cancer, but without the mutation. This suggests the establishment of viral infection and the development of tumors sharing common pathways.

"We thought there should be more proteins that can cause cancer by being mutated or diverted by HPV, so we developed a new method to detect them," said Eckhardt. "Our study has highlighted two interesting cases where the interaction of HPV and human proteins plays a role in the development or invasion of cancer."

Eckhardt has shown that the HPV E1 protein interacts with the human KEAP1 protein, which is often mutated in smoking-related cancers. In HPV-positive cancers, KEAP1 is not mutated. But, thanks to its interaction with the E1 protein, KEAP1 is inactivated, which helps the cancer cells to survive.

The researchers also discovered that the HPV L2 protein, which is part of the virus's packaging, interacts with two human proteins called RNF20 and RNF40. They have shown that in HPV-positive cancers, this protein interaction increases the tumor's ability to spread and invade new parts of the body.

These results confirm that the HPV virus causes head and neck cancers by targeting the same proteins that react poorly to mutations induced by smoking.

Linking cancer and infectious diseases

Krogan and colleagues have shown that integrating HPV-human interaction with tumor genome data and focusing on mutated genes in negative but not positive HPV tumors is a powerful approach to identifying proteins. cancer drivers.

The scientists' work should pave the way for better treatment options for HPV and HPV-negative head and neck cancers. In addition, Krogan's long-term goal is to define a pipeline that will investigate many other cancers of viral origin, including those related to hepatitis B and C, Epstein-Barr virus and adenoviruses.

"Science can be compartmentalized and, through these unbiased and comprehensive approaches, we can begin to find common pathways between different systems," said Krogan, who also leads Host Pathogen Map Initiative, which aims to compare protein and genetic interactions between similarities. "Our work is helping to connect the dots between cancer and infectious diseases in a way that has never been considered."