Scientists at New York University Langone Health and its Perlmutter Cancer Center have mapped how pancreatic ductal adenocarcinoma continually changes its genetic makeup as it becomes more aggressive, spreads and resists treatment. By analyzing gene activity in 443,451 individual cancer cells from 62 tumors, the researchers identified distinct cancer cell populations and genetic changes—including activity involving MYC and TIGIT—that could point to new treatment strategies for one of the deadliest cancers.
How pancreatic cancer evolves
The study focused on pancreatic ductal adenocarcinoma, a particularly difficult cancer to treat. Almost 85% of patients die within five years of diagnosis.
Researchers have already linked more than six genes to the disease, but much remains unknown about how pancreatic cancer develops and adapts. By studying tumor cells individually rather than in large groups, the team was able to examine how different cancer cell populations change their DNA as the disease progresses.
Pancreatic tumors contain multiple distinct cell populations, known as clones. Each clone consists of cancer cells with similar genetic characteristics, but the behavior of those cells can vary widely.
Some clones acquire changes that help them withstand cancer treatment, while others become more capable of invading nearby tissue and spreading to other parts of the body. The findings suggest that cancer’s ability to continually rearrange its genetic material plays a central role in treatment resistance and metastasis.
Previous studies generally divided pancreatic cancer cells into two main categories: classic, which is less malignant, and basal, which is more malignant. However, because those studies examined large collections of cells together, they could not fully explain how cancer cells move from one category to the other.
The new findings provide clues about this process. Genetic changes that occur within individual tumors may allow cancer cells to transition between the classic and basal states, increasing the risk posed by the disease as it progresses.
MYC may help make pancreatic cancer less aggressive
Published on October 13 in Nature Genetics, the study identified several genetic changes associated with pancreatic cancer progression. One of the most important findings involved the MYC gene, which showed increased activity in some of the most aggressive cancer cell populations.
In additional laboratory experiments, the researchers blocked MYC activity in aggressive basal pancreatic cancer cells. The cells reverted to a less aggressive classic state.
The researchers suggested that this change may make the cancer cells more visible to immune cells, allowing the immune system to recognize and attack them more easily. Although further research is needed, the result indicates that MYC could be a promising target for future pancreatic cancer treatments.
“Our study provides the most detailed view to date of pancreatic ductal adenocarcinoma and reveals how ongoing genetic remodeling drives tumor evolution throughout the course of the disease,” said study principal investigator Despoina Kalfa-Kakou, Ph.D., a postdoctoral fellow at New York University’s Grossman School of Medicine and Perlmutter Cancer Center. “These findings suggest that targeting mechanisms underlying tumor evolution, including MYC, may help suppress rapid cancer progression.”
“Our study also suggests that single-cell clonal analysis provides a better approach to understanding complex cancers like pancreatic ductal adenocarcinoma that progress over time by mapping how tumors evolve and adapt at each stage of disease progression,” said study co-senior investigator Aristotelis Tsirigos, Ph.D., professor in the Department of Medicine and Pathology at NYU Grossman School of Medicine and a member of the Perlmutter Cancer Center.
“More broadly, our findings highlight the important roles that clonal diversity, genetic plasticity, and interactions with the tumor microenvironment play in shaping the biology of human pancreatic ductal adenocarcinoma,” said Tsirigos, co-director of the Division of Precision Medicine and director of the Applied Bioinformatics Laboratory at New York University Langone.
Why pancreatic cancer can evade the immune system
The study also offered clues about how pancreatic cancer hides from the immune system, which may help explain why the disease responds poorly to immunotherapy.
Some cancer cell clones showed increased activity of the TIGIT gene, which is associated with a protein that helps tumors evade immune detection. At the same time, those clones showed reduced activity of the PD1 gene.
This combination may help explain why immunotherapies designed to target PD1 have shown limited effectiveness against pancreatic cancer. Understanding the differences between cancer cell populations could help researchers develop treatments that interfere with the specific mechanisms tumors use to avoid immune attack.
Tsirigos said clinical trials are already investigating drugs that inhibit MYC or TIGIT in pancreatic ductal cancer and other cancers. He said the findings underscore the need for large-scale studies that account for the different states cancer cells can occupy and identify ways to tailor treatments to those states.
Nearly 500,000 cells reveal tumor diversity
To study how pancreatic cancer changes over time, the researchers used transcriptomics to measure gene activity in 443,451 individual cells taken from 62 tumors from 56 men and women diagnosed with pancreatic ductal adenocarcinoma.
Six of the patients also provided tumor samples before and after chemotherapy, allowing the researchers to examine changes associated with treatment.
Unlike conventional methods that measure gene activity across large groups of cells, the new analysis examined individual cells. This provided a more detailed view of the different cancer cell populations within the same tumor.
The results showed that individual tumors contained approximately two to 11 different clones, made up of varying combinations of classic and basal cancer cells.
By tracing the genetic origins of these clones and comparing patterns of gene activity, the researchers linked differences in DNA copy number to the types of cells found in each tumor. This approach helped identify genes such as MYC and TIGIT that are particularly active at different points in cancer progression.
Together, the findings provide a more detailed picture of how pancreatic tumors progress, resist treatment and spread. They also suggest that interfering with the genetic mechanisms driving these changes could create new opportunities to treat a disease that remains extremely difficult to control.
Research funding and team
The research was supported by the Sky Foundation and National Institutes of Health grants P30CA016087 and R01CA245005.
In addition to Kalfa-Kakou and Tsirigos, the New York University Langone research team included Daniel Cameron, M.A.; Emily Kawaler, M.D.; Ziaohong Jing, Ph.D.; Christina H. Hajdu, M.D.; Dylan Tamayo; Yuna Shim; Amanda Ackerman, M.D.; Daniel Weissinger; Rosmel Hernandez; Matthew Baier, M.D.; Dacia DiMartino; Peter Mine; Karina Rice; Shanmugapriya Selvaraj; Cynthia A. Loomis, M.D.; Adriana Hegay, Ph.D.; Amanda W. Rand, Ph.D.; and Igor Dolgalev.
Additional contributors from Oregon Health & Science University included co-investigator Motoyuki Tsuda, M.D.; Hayley Jimny; and Rosalie Sears, Ph.D.
Researchers from the University of California, San Diego included Lidong Wang, Ph.D.; Qi Su, Ph.D.; Kim Sung-sik, M.D.; Hannah Carter, Ph.D.; Theodore Welling, M.D.; and co-senior investigator Diane Simeone, M.D.
Source: www.sciencedaily.com