This “master gene” may be driving pancreatic cancer’s spread

"Epigenetic alterations are underappreciated as a major route to developing and fueling the growth of cancer metastasis," says Andrew Feinberg, M.D., Bloomberg Distinguished Professor in the Johns Hopkins University schools of medicine, engineering and public health.

Feinberg and his colleagues previously reported in 2017 that the most common form of pancreatic cancer shows widespread epigenetic changes in primary tumors. These changes, rather than new DNA mutations, appeared to drive the cancer's ability to spread throughout the body.

The latest findings, published in Molecular Cancer and supported in part by the National Institutes of Health, build on that earlier work and point to new possibilities for treatment.

CRISPR Study Pinpoints Key Cancer Gene

To identify which genes are most important for cancer cell growth, the research team used CRISPR, a gene-editing technology that can selectively turn genes off. By systematically silencing genes, the scientists observed which ones had the greatest impact on slowing or stopping cancer cell growth.

Among all the genes tested, KLF5 stood out. It had the strongest effect on promoting the growth and spread of metastatic cancer cells. In samples from patients, 10 of 13 individuals with pancreatic cancer showed higher levels of KLF5 activity in at least one metastatic tumor compared with their original tumor.

KLF5 Controls DNA Packaging and Gene Activity

Further experiments confirmed that KLF5 influences how tightly DNA is packed inside cells. This packaging plays a critical role in determining which genes are active and which remain silent.

The researchers found that even small increases in KLF5 activity could significantly boost a cancer cell's ability to grow and spread. "This could suggest that, to develop treatments for pancreatic cancer metastasis, the gene may not need to be entirely shut down to have a positive effect," says Feinberg. He also notes that several experimental drugs designed to target KLF5 are already under development.

Additional Genes Linked to Cancer Spread

The study also showed that KLF5 regulates other genes, including NCAPD2 and MTHFD1, but only in metastatic pancreatic cancer cells, not in primary tumor cells grown in the lab. These genes are known as epigenetic modifier genes because they influence gene activity by adding chemical groups to DNA and altering its structure.

"We are adding to evidence that cancer metastases are not caused by additional mutations in the primary cancer, but by additional epigenetic changes, enabling the cancer to thrive and grow," says first author Kenna Sherman, a graduate student in the Johns Hopkins Human Genetics and Genomics program. "KLF5 seems to be a master gene that drives such changes and impacts a pathway of genes known to control invasion and the ability to resist treatments."

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 the 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 Hopins; Xingbo Shang and Andre Levchenko from Yale University; and Jimin Min and Anirban Maitra from NYU Langone Health.