Study challenges potential pancreatic cancer target

January 17, 2017
Credit: University of Michigan Health System

A protein thought to fuel pancreatic cancer development plays a much more complicated role, a new study finds.

PDX1, a transcription factor critical for pancreatic development, has distinct roles at different stages of - keeping at bay in normal cells, then eventually contributing to the cancer's growth once a tumor forms, but also preventing the tumor from becoming more aggressive.

It's a complexity that seems to be typical of this challenging disease, which is the No. 3 cancer killer.

Researchers from Michigan Medicine and the University of California-San Francisco used mouse models to look at normal pancreas cells, a type of pre-cancerous pancreas lesion called PanIN, and pancreatic cancer cells. In the , PDX1 maintains the cells' identity as pancreas cells and epithelial cells. The protein is required for a wound-healing process to regenerate the damaged organ and maintain normal cell function.

But once cells become malignant, PDX1 takes on a new role and contributes to the cancer's growth. This activity has made it an attractive target for developing potential pancreatic cancer treatments: Block PDX1 and the cancer won't grow.

This new study, published in Genes and Development, finds a significant twist.

When researchers looked at subtypes of pancreatic cancer, they found the lowest levels of PDX1 were actually in the most aggressive cancers. The patients whose tumors had no PDX1 had the worst outcomes.

"PDX1 has been reported as a target to treat cancer. The reality is that might not be the best idea," says study author Howard Crawford, Ph.D., professor of molecular and integrative physiology and of internal medicine at the University of Michigan Medical School.

While the protein functions to promote the cancer's growth, ultimately, Crawford explains, turning off PDX1 makes the cancer more aggressive.

"We showed the loss of PDX1 is actually promoting the aggressiveness. Losing PDX1 means the cells lose their identity," Crawford says.

The researchers found that this loss of identity allows the relatively well-behaved to transition to bad-acting mesynchemal cells, which are more likely to move throughout the body - the hallmark of metastatic cancer, which is the primary cause of cancer recurrence and patient death.

When PDX1 is lost, the researchers found, it selects for cancer that express MYC, which is known to be involved in cancer growth and metastasis.

"We need to be cautious about targeting PDX1. If we do target it, the cancer will escape treatment by upregulating MYC, so we need to be prepared to target that too," Crawford says. Inhibitors are being developed that have shown some effect on cancers expressing MYC.

Crawford compares PDX1 to the estrogen receptor in breast cancer or the androgen receptor in prostate cancer. Both define cell identity and are legitimate targets for treatment. But in both cases, tumors can become resistant to treatments - leading to the most challenging and aggressive types of those cancers.

"Inhibiting PDX1 can be temporarily effective. But we need to be prepared for the mechanism of resistance and for the likelihood of making the cancer more aggressive," Crawford says.

Explore further: A master gene determines whether cells become pancreatic or liver cells

More information: Nilotpal Roy et al, PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance, Genes & Development (2017). DOI: 10.1101/gad.291021.116

Related Stories

A master gene determines whether cells become pancreatic or liver cells

July 15, 2015
A gene in human embryonic stem cells not only steers them to form a pancreas but simultaneously prevents them from becoming liver cells, A*STAR researchers have shown. This discovery is an important step toward growing functioning ...

Starving pancreatic cancer cells: Scientists identify potential pancreatic cancer target

October 17, 2016
Researchers have found that a protein called SLC6A14 is overexpressed by several fold in pancreatic tumors taken from patients and in cancerous pancreatic cells lines compared with normal pancreatic tissue or normal pancreatic ...

Aspirin slows growth of colon, pancreatic tumor cells

December 15, 2016
Researchers from Oregon Health and Science University and Oregon State University have found that aspirin may slow the spread of some types of colon and pancreatic cancer cells. The paper is published in the American Journal ...

Reason for pancreatic cancer's resistance to chemotherapy found

November 21, 2016
A pioneering University of Liverpool research team have published a study that identifies the mechanism in the human body that causes resistance of pancreatic cancer cells to chemotherapy.

Protein found to play key role in the spread of pancreatic cancer

April 18, 2016
Researchers from the University of Liverpool working with colleagues from around the globe have found an explanation for how pancreatic cancer spreads to the liver. These findings potentially hold the key to stopping this ...

Recommended for you

Study suggests colon cancer cells carry bacteria with them when they metastasize

November 24, 2017
(Medical Xpress)—A team of researchers working at Harvard University has found evidence that suggests a certain type of bacteria found in colon cancer tumors makes its way to tumors in other body parts by traveling with ...

Promising new treatment for rare pregnancy cancer leads to remission in patients

November 24, 2017
An immunotherapy drug can be used to cure women of a rare type of cancer arising from pregnancy when existing treatments have failed.

Researchers unravel novel mechanism by which tumors grow resistant to radiotherapy

November 23, 2017
A Ludwig Cancer Research study has uncovered a key mechanism by which tumors develop resistance to radiation therapy and shown how such resistance might be overcome with drugs that are currently under development. The discovery ...

African Americans face highest risk for multiple myeloma yet underrepresented in research

November 23, 2017
Though African-American men are three times more likely to be diagnosed with multiple myeloma, a type of blood cancer, most scientific research on the disease has been based on people of European descent, according to a study ...

Encouraging oxygen's assault on iron may offer new way to kill lung cancer cells

November 22, 2017
Blocking the action of a key protein frees oxygen to damage iron-dependent proteins in lung and breast cancer cells, slowing their growth and making them easier to kill. This is the implication of a study led by researchers ...

One-size treatment for blood cancer probably doesn't fit all, researchers say

November 22, 2017
Though African-American men are three times more likely to be diagnosed with a blood cancer called multiple myeloma, most scientific research on the disease has been based on people of European descent, according to a study ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.