Metastatic cancer cells thrive in harsh microenvironments

A group of breast cancer cells, born from the abnormal genomics of one cell, grows and multiplies, becoming a tumor. As that tumor thrives in its primary environment, a handful of cells may break away. These malignant pioneers are on a journey to take over their host – to metastasize. To travel to a faraway part of the body and establish themselves there, the cells undergo a perilous trip. They must detach from the main tumor, infiltrate the blood stream, survive long enough to arrive at their new destination and successfully plant their seeds in a new organ or tissue to grow into a metastatic tumor site. The process is difficult, and not all cancer cells are up to the task of metastasizing. But what distinguishes the cells that are? And how can they be stopped?

“The overarching goal of our lab is to understand how metastasis works, so that we can eventually target it therapeutically,” said Myriam Labelle, PhD, St. Jude Department of Oncology. “This is important and likely to have an impact on patients because most cancer-related deaths are due to metastasis, and there are no cures targeting this process.”

Labelle’s lab at St. Jude has put together some of the puzzle pieces to help answer the questions of what helps cells successfully metastasize. Recently published in Science Advances, Labelle’s lab revealed an epigenetic mechanism that assists cells during metastasis. Epigenetics refers to processes that affect the way genes are expressed, but which do not directly involve mutations to DNA itself. For example, the mechanisms that govern transcription are generally considered epigenetic.

Transcription is an essential biological process where DNA is copied into RNA. The process is the first required step in a cell to take the instructions housed in DNA and ultimately make active proteins. Dysregulated transcription plays a role in many types of cancer. Labelle’s team identified that inhibition of a specific transcriptional regulator, called ZBTB18, can allow cancer cells to successfully metastasize.

“There's really a complexity to it that is coming from both the tumor cells and the microenvironment, but we found that a decline in the activity of the transcriptional repressor ZBTB18 defines metastasis-competent cancer cells in our models,” Labelle said.

A metastatic mechanism revealed

Labelle and her team set out to understand the requirements for metastasis, the factors that cells need to successfully adapt to the different environments that they encounter during the process. To find the epigenetic basis of metastasis, the lab developed two new breast cancer cell lines. One of the lines they developed was significantly more metastatic than any other comparable line, and the other was more aggressive in terms of primary tumor growth but generated almost no metastases. Comparing the different cell lines led the researchers to ZBTB18.

ZBTB18 was a known transcriptional suppressor, which squashed the expression of many genes.

This is the first study that links ZBTB18 to metastasis. The researchers evaluated how it subdued the expression of genes. They noticed that it also condenses chromatin, the biologic spools around which DNA is wound. When chromatin is condensed, gene expression is lowered.

The researchers’ experiments suggest that the activity of ZBTB18 is lost in highly aggressive tumor cells. This would mean that chromatin is more open, enabling transcription factors to come in and activate different programming that would help the cell adapt to changing environmental conditions. For example, without ZBTB18 activity, chromatin is more open, allowing access to the promoters of genes that drive metastasis, such as Tgfbr2. Access to Tgfbr2 can lead to the activation of the TGFβ1 pathway that promotes the cell migration and invasion seen in metastasis.

“ZBTB18 is a potent chromatin regulator, and loss of its activity enhances chromatin accessibility and transcriptional adaptations that promote the phenotypic changes required for metastasis,” Labelle said.

The findings suggest that it could be beneficial therapeutically to target the processes that sequester ZBTB18 in the nucleus, and this could be a future area of study for the Labelle lab.

“There's a lot of possibilities for where this could go,” she added.

The first author of the study is Ruishan Wang, PhD, St. Jude Comprehensive Cancer Center Solid Tumor Program and St. Jude Department of Developmental Neurobiology