Why pancreatic ductal adenocarcinoma is so lethal

May 19, 2020

Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer, killing patients within a year. CSHL Professor Christopher Vakoc and his former postdoc Timothy Somerville discovered how pancreatic cells lose their identity, acquire a deadly new identity, and recruit nearby cells to help them grow, promote inflammation, and invade nearby tissues. This understanding could lead to new therapies similar to ones developed for other cancers.

Vakoc says, "We think part of the reason why these tumors are so aggressive is that they exploit normal cells. The normal cells that are in the vicinity of these tumors, are actually co-conspirators in this disease, and are being co-opted to kind of create a community of cells that are kind of teaming up with one another to drive this aggressive cancer to expand and metastasize. Ultimately, we think we sort of learned why this tumor is so aggressive through understanding these two mechanisms."

Somerville found two transcription factors that were highly abundant in PDA but not in a normal pancreas: ZBED2 (pronounced Z-bed too) and p63.

ZBED2 confuses the pancreas cell about its own identity. It displaces another transcription factor that is required for the pancreas cell to perform its normal functions as a pancreas cell. ZBED2 turns pancreas cells into squamous cells--a type of cell found in the skin. Patients with the worst outcomes have the highest levels of squamous cells in their tumors.

Little was known about ZBED2 when Somerville began his research. He says, "ZBED2 is a gene. It makes a protein, which is transcription factor ZBED2. What was completely unknown was what this protein ZBED2 was actually doing. We were able to demonstrate that it is a transcription factor, which means that it can bind to DNA and regulate other genes. And we were able to show what types of genes it regulates."

p63 recruits nearby cells--mostly neutrophils and fibroblasts--to support the cancerous squamous cells. They "alter the tumor microenvironment, making it more inflammatory and more aggressive. This is what we think is contributing to the particularly poor outcomes of this group of pancreatic patients," says Somerville.

PDA is notoriously resistant to chemotherapy. The wall of inflammatory cells makes it difficult for anti-tumor drugs to access the tumor. Somerville believes that understanding what ZBED2 and p63 are doing to make this cancer so aggressive will uncover ways that scientists can prevent or at least slow its growth. Somerville notes, "It's about exploiting transcription factors. If we understand their functions, we can use them to show us how to think about different ways to treat this disease."

The FDA has already approved drugs that target transcription factors in breast cancer, leukemia, and prostate cancer. Vakoc's lab is seeking to advance this concept for other types of cancer, such as PDA.
-end-
Funders: CSHL Cancer Center, CSHL Association, the State of New York, the Lustgarten Foundation, the Pershing Square Sohn Cancer Research Alliance, the CSHL & Northwell Health Affiliation, the National Cancer Institute, the Thompson Family Foundation, the Simons Foundation, NIH, Pancreatic Cancer Action Network of the AACR, EMBO, the Human Frontiers Science Program, and Deutsche Forschungsgemeinschaft.

Cold Spring Harbor Laboratory

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.