Scientists at Johns Hopkins School of Medicine have identified a gene that appears to play a key role in the spread of pancreatic cancer. In cells grown in the lab, the gene KLF5 (Kruppel-like factor 5) was found to promote tumor growth and invasion by changing how DNA is organized and chemically modified, rather than by changing the DNA sequence itself. These epigenetic changes control whether genes are switched on or off.
“Epigenetic changes are an underappreciated key pathway in developing cancer metastases and promoting proliferation,” says Andrew Feinberg, MD, PhD, Bloomberg Distinguished Professor in the Johns Hopkins School of Medicine, Engineering, and Public Health.
In 2017, Feinberg et al. reported that the most common type of pancreatic cancer has extensive epigenetic changes in the primary tumor. These changes, rather than new DNA mutations, appear to facilitate the cancer’s ability to spread throughout the body.
The latest findings, published in the journal Molecular Cancer and supported in part by the National Institutes of Health, build on previous research and point to new possibilities for treatment.
CRISPR research identifies key cancer genes
To identify which genes are most important for cancer cell growth, the research team used CRISPR, a gene-editing technique that can selectively turn off genes. By systematically silencing genes, scientists observed which genes had the greatest impact on slowing or stopping the growth of cancer cells.
Among all the genes tested, KLF5 stood out. It had the most powerful effect in promoting the proliferation and metastasis of metastatic cancer cells. In samples taken from patients, 10 out of 13 pancreatic cancer patients showed elevated levels of KLF5 activity in at least one metastatic tumor compared to the original tumor.
KLF5 controls DNA packaging and gene activity
Further experiments confirmed that KLF5 affects the density of DNA within cells. This packaging plays an important role in determining which genes are active and which are silent.
Researchers have found that even small increases in KLF5 activity can significantly increase a cancer cell’s ability to proliferate and metastasize. “This may suggest that to develop treatments for pancreatic cancer metastases, it may not be necessary to completely block the gene to have a positive effect,” Feinberg says. He also noted that several experimental drugs designed to target KLF5 are already in development.
Additional genes associated with cancer prevalence
The study also showed that KLF5 regulates other genes, such as NCAPD2 and MTHFD1, but only in metastatic pancreatic cancer cells and not in primary tumor cells grown in the lab. These genes are known as epigenetic modification genes because they affect the activity of genes by adding chemical groups to DNA and changing its structure.
“There is growing evidence that cancer metastasis is not caused by additional mutations in the primary cancer, but rather by additional epigenetic changes that enable the cancer to proliferate and grow,” says first author Kenna Sherman, a graduate student in the Human Genetics and Genomics Program at Johns Hopkins University. “KLF5 appears to be a master gene that drives such changes and influences pathways of genes known to control invasion and the ability to resist treatment.”
Funding and research team
This research was supported by the National Institutes of Health (CA54358, R01HG010889, R01HG013409, T32GM148383), a Celgene License Pathway Agreement, and a gift from the friends and family of Jasmine Lampadarios.
Additional contributors to this study include Masahiro Maeda, Weiqiang Zhou, Jiaqi Cheng, Yuta Nihongaki, Adrian Idrizi, Rakel Tryggvadottir, Oscar Camacho, Michael Koldobskiy, Barbara Slusher and Hongkai Ji from Johns Hoppins. Shimbo Shan and Andre Levchenko of Yale University; Jimin Min and Anirban Maitra of NYU Langone Health;
