Pancreatic cancer cells are 'addicted' to key protein

Pancreatic cancer is particularly difficult to treat.

(Online) - New research finds that the cancer cells in a particularly aggressive form of pancreatic cancer rely heavily on a key protein to grow and spread. The findings may soon lead to new treatments and prevention strategies.

Pancreatic cancer is particularly difficult to treat. The American Cancer Society estimate that up to 61 percent of people with early-stage pancreatic cancer live for at least 5 years after diagnosis.

Some subtypes of pancreatic cancer are more aggressive than others. For example, pancreatic ductal adenocarcinoma is usually already at an advanced stage when doctors detect it, and its 5-year survival rate is less than 10 percent.

However, new research may have identified the main weakness of this aggressive form of cancer, which is that its cells are addicted to a key protein.

Dr. Christopher Vakoc, PhD, a professor at the Cold Spring Harbor Laboratory in New York, and his team investigated the reason why this subtype of pancreatic cancer is so aggressive.

Until now, the researchers knew that a certain mutation was to blame for the progression of the disease, but they did not know exactly what triggered the mutation in the first place.

In the new study, they find a gene encoding a protein that is highly expressed in this particularly aggressive cancer.

Timothy Somerville, a postdoctoral fellow in Prof. Vakoc’s laboratory, is the lead author of the new paper, which was recently published in the journal Cell Reports.

Somerville explains that a person with a pancreatic cancer diagnosis goes on to live for an average of 2 years. However, those in the small subset of people with pancreatic ductal adenocarcinoma have a much less favorable outlook of under a year.

"This version of the cancer is especially deadly," notes Somerville. The researchers in Prof. Vakoc’s team hypothesized that a specific protein may be responsible for making this cancer so aggressive.

To determine which protein it was, the researchers used existing "transcriptome analyses of [pancreatic ductal adenocarcinoma] tumors" in search of a transcription factor that acts as a "master regulator."

Transcription factors are "key proteins that decode the information in our genome to express a precise and unique set of proteins and RNA molecules in each cell type in our body." They contain domains "that bind to the DNA of promoter or enhancer regions of specific genes."

In the case of pancreatic cancers, the researches believed that the "master regulator transcription factor" would give the pancreatic ductal adenocarcinoma its squamous quality.

[The analyses revealed] a gene [and the protein it produces] called Tumor-Protein 63 (TP63) that is specifically expressed in this aggressive form of pancreatic cancer," says Somerville.

As the researchers explain, the P63 protein does not usually belong in the pancreas. Instead, its main role is to help create specialized skin cells called squamous cells. In pancreatic ductal adenocarcinoma, the new study revealed, this protein made pancreatic cells transform into something they should not

To replicate their findings, the researchers studied the behavior of this protein further using "human organoid cultures derived from normal pancreatic tissue or [pancreatic ductal adenocarcinoma] tumors."

These analyses revealed that the presence of TP63 within the tumor enabled cancer cells to grow, multiply, and migrate to other parts of the body. However, TP63’s "help" came at a price for the cancer cells.

"One of the encouraging findings is that when this happens," explains Somerville, "the cancer cells become so reliant on P63 that they actually require P63 for their continued growth."

"So moving forward, we’re looking into approaches to suppress inappropriate P63 activity as a treatment option for patients."

The lead author adds that understanding why the P63 gene becomes active in certain individuals would lead to valuable preventive measures. This is the next goal for the research team.

"If we can stop it from ever happening," Somerville says, "it could be really good for the survival of this most vulnerable group of cancer patients."