Research News

Left: Immune cells (light purple) with round nuclei (dark purple). Right: A process called loop extrusion has been blocked, changing the nuclei of these cells to a flower-like shape.

Researchers have uncovered a potential strategy that cells use to organize their DNA and determine the shape of their nuclei. The findings, published in Nature, have far-reaching implications for how researchers can interact with and modify cells like immune cells and cancer cells, and lay the groundwork to genetically engineer new types of therapeutics. 

Some types of cells change the shape of their nuclei to make it easier to fit through our body's tissues. Understanding this process could help block dangerous cells from causing disease or designing therapeutics to reach specific targets. 

"These types of treatments have been considered science fiction for years," says Ming Hu, PhD, co-corresponding author of the study. "Our discovery is the first step to making the fiction a reality." 

The research project began as a collaboration between Dr. Hu, Associate Staff in Quantitative Health Sciences, and Cornelis Murre, PhD, Professor of Immunology at University of California, San Diego. Dr. Hu is a member of the Center for Integrated Multi-Modal and Multi-Scale Nucleome Research, a multi-consortium NIH grant awarded to better understand how our DNA is organized within our cells and how the physical space our DNA occupies governs human health and disease.

The team studied DNA storage and nucleus shape in immune cells called neutrophils. While it is well established that cells must physically coil, fold and organize their DNA to fit inside their nuclei, the impact that the "folding method" has on nuclear shape has remained elusive.

In neutrophils, the answer lies in loop extrusion 

The team focused on a group of cells named neutrophils, immune cells that travel through our tissues to respond to threats like infection and pre-cancerous cells. Neutrophils store their DNA in multi-lobular nuclei that resemble flower petals. Unlike round nuclei often shown in biology textbooks, multi-petalled nuclei take up less physical space within the cell and are more malleable. This change in shape grant cells the flexibility they need to shrink, squeeze and change shape as they migrate through the difficult terrain of our tissues.

Dr. Hu and Murre found blocking a process called loop extrusion converts round nuclei to multi-petaled nuclei. Loop extrusion folds the DNA into thousands of tightly-packed loops, reorganizing the cell's genome and bringing genes that are spatially far apart on a DNA strand into physical contact. Once loop extrusion is blocked, the cells' DNA instead forms more loosely-packed "mega loops" and their nuclei are more flexible like a neutrophil's. 

"We used neutrophils in our studies because they represent an extreme. The nucleus shape is easy to identify under a microscope, so they are easier to study." says Dr. Murre. "By looking at extremes, we hope to find general principles that guide the interconnected tenants of DNA packaging, nuclear shape and cell migration." 

Drs. Hu and Murre aim to follow up on their findings to see if loop extrusion plays a role in the development of a far more dangerous cell type: cancer cells. 

Shaping the future of cancer treatments 

When tumors become metastatic, cancer cells travel away from their initial location to a second part of our bodies. If the cancer isn't already part of the bloodstream or lymphatic system, its cells must squeeze through the gaps between tissue cells as they migrate away from the tumor. One of the key steps during the transformation from benign to metastatic cancer happens when a cancer cell gains the ability to travel through our body's tissue through repackaging DNA, Dr. Hu says. Cancer cells whose nuclei become more malleable can travel through tissue more easily and are thus more likely to become metastatic.

Now that we know loop extrusion is an important factor in repackaging DNA and reshaping the nucleus in neutrophils, we can begin tests to see whether it is important in metastatic cancer cells and whether the process is a viable target to manipulate during treatment, Dr. Hu says. Drs. Hu and Murre also hope to one day use loop extrusion to genetically engineer better immunotherapies for treatment-resistant cancers.

Immunotherapies like CAR-T genetically engineer a patient's own T-cells (a type of immune cell) to better recognize and fight off cancer. These treatments are lifesaving for many individuals with tumors that don't respond to radiation or chemotherapy, but the fact remains that not all patients respond to immunotherapy. Drs. Murre and Hu will investigate whether manipulating loop extrusion in T-cells can change their nuclear shape and grant them the ability to enter and destroy solid tumors. 

"Genetic engineering can be a powerful tool, but our power only extends as far as our knowledge of genetics," says Dr. Hu. "We now have a map forward to understand some of the most basic and powerful genetic tenants of all: the physical shape of our DNA."