MSK scientists learn how genes and environment conspire in pancreatic cancer development

February 03, 2021

Like weeds sprouting from cracks in the pavement, cancer often forms in sites of tissue damage. That damage could be an infection, a physical wound, or some type of inflammation. Common examples include stomach cancer caused by H. pylori infection, Barrett's esophagus caused by acid reflux, and even smoking-induced lung cancer.

Exactly how tissue damage colludes with genetic changes to promote cancer isn't fully understood. Most of what scientists know about cancer concerns advanced stages of the disease. That's especially true for cancers such as pancreatic cancer that are usually diagnosed very late.

Researchers in Scott Lowe's lab at the Sloan Kettering Institute are now trying to zero in on the earliest stages of pancreatic cancer development.

"If we understood how these tumors form, maybe we could catch them before the cancer has progressed to an incurable stage," says Direna Alonso Curbelo, a postdoctoral fellow in the Lowe lab who is the first author of a new paper published February 3 in Nature.

Using advanced genomic techniques and innovative mouse models, the researchers were able to discern how tissue damage synergizes with specific genetic changes to promote the earliest stages of pancreatic cancer.

Wound Repair Gone Wrong

It starts with the activation of a normal repair process in response to damage -- damage, it turns out, that can be inflicted by the pancreas's own digestive enzymes.

"The pancreas is like a mini factory of enzymes made to break down food," Dr. Alonso Curbelo says. "If these enzymes are released out of place, they can degrade the tissue and cause pancreatitis [a form of inflammation]."

Fortunately, the pancreas is really good at repairing itself. During the repair response, the cells in the damaged area change their behavior. They temporarily shut down their production of digestive enzymes and take on a different form. They return to their normal functioning once the damage has been resolved. At least, that's what's supposed to happen.

But when these damaged cells also contain a genetic mutation in a gene called KRAS, the wound-healing response goes haywire and the cells never return to normal. Mutant KRAS is known to drive tumor growth in 95 percent of people with pancreatic cancer, but it has so far been unclear how mutant KRAS derails the wound-healing process to initiate the disease.

Dr. Alonso Curbelo and colleagues were able to identify what distinguishes the normal repair process from the cancer-initiating one at the molecular level. They found major changes in how chromatin is organized that were uniquely induced in damaged KRAS-mutant cells. (Chromatin is the combination of DNA and proteins that make up chromosomes.) As a result of these changes, different genes are turned on and off, and the cells take on early cancerous properties.

Opening the Wrong Instructions

Think of the process like opening and closing a zip file. Parts of a chromosome that should be open for normal pancreatic function are inadvertently zipped. Conversely, other parts that are usually zipped are opened. As a result, the wrong set of genetic instructions is available to the damaged cell, which gets confused about its identity.

The whole process happens very quickly. Researchers found that over half of the chromatin changes that typically characterize advanced pancreatic cancer were already present in these cells within 48 hours of tissue damage. Because these cancer-associated changes in gene expression are not caused by changes in DNA sequence, they are called epigenetic (epi meaning beyond, genetic meaning genes).

This discovery is important because it suggests that scientists could potentially block cancer development by interfering with the activation of genes that become inappropriately turned on. And indeed, the team showed that they could do just that: When they prevented their activation in the damaged cells in the mice, the initiation of pancreatic cancer was blunted.

It Takes Two

Interestingly, these early, cancer-associated epigenetic changes did not occur when either mutant KRAS or tissue damage were present separately. Only the combination triggered it.

"Our study provides some understanding of why cancers often arise at sites of tissue damage," Dr. Lowe says. "You need both a mutated gene and tissue damage to activate the epigenetic program that drives cancer initiation. Each alone does not do it."

The discovery of epigenetic changes at the heart of cancer initiation, and their high degree of specificity, opens up the possibility that scientists could try to target these newly turned-on genes as a way to selectively interrupt cancer development.

As well, scientists might one day be able to use these genes as markers to identify early signs of cancer and intervene before it's too late.
-end-
This research was supported by the NCI Cancer Center Support Grant (P30 CA08748), the National Institutes of Health (NIH; grants F31CA246901, F99CA245797, K99CA237736, 1F32CA177072-01, K99CA23019, P01CA13106, R01CA204228, P30CA023108, and U54CA209975), Cycle for Survival, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, the Spanish Fundación Ramón Areces, the American Cancer Society, the Pancreatic Cancer Action Network-AACR Pathway to Leadership Award, the Jane Coffin Childs Memorial Fund for Medical Research, the David Rubenstein Center for Pancreatic Research, the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, the Lustgarten Foundation, and the Agilent Thought Leader Program. Dr. Lowe is an investigator in the Howard Hughes Medical Institute and the Geoffrey Beene Chair for Cancer Biology. A patent application has been submitted based in part on results described above. Dr. Curbelo and Dr. Lowe are listed as the inventors. Dr. Lowe is a founder and scientific advisory board member of Blueprint Medicines, Mirimus Inc., ORIC pharmaceuticals, and Faeth Therapeutics, and on the scientific advisory board of Constellation Pharmaceuticals and PMV Pharmaceuticals.

Memorial Sloan Kettering Cancer Center

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.