A Closer Look at Cancer: One Cell at a Time

A few years ago, Jerry Shay, PhD, and Woodring Wright, MD, PhD, both Professors of Cell Biology, developed a powerful new tool in cancer research – a way to culture normal colon cells.

Thanks to this technique, they have a way to test, one trait at a time, which genetic mutations are important for the varied behavior of cancerous cells. The method is so powerful that researchers around the world have requested samples of the cells for their own work.

“Everything I do may be forgotten, but my cells, distributed to hundreds of labs, will be part of my legacy,” Dr. Shay said.

(L-R) Woodring Wright, MD, PhD, and Jerry Shay, PhD

Drs. Shay and Wright’s research focuses on a portion of the chromosomes called telomeres. Telomeres consist of a repeated section of DNA that “caps” the ends of chromosomes. Every time a cell divides, its telomeres shorten. When the telomeres become short enough, the cell stops dividing and instead ages, changing the type of proteins made.

An enzyme called telomerase adds DNA back on the telomeres, maintaining their length and allowing cells to keep dividing. Telomerase plays a valuable role during development but has a darker side: If it is inappropriately active, it can “immortalize” cells to divide indefinitely, and this is permissive for cells becoming cancerous.

Drs. Shay and Wright and their colleagues were able to take advantage of telomerase’s action, and by expressing it in normal human colon cells, they were able to create cells that could divide indefinitely in culture, but were not cancerous. 

This allowed them to tackle cancer a new way – mutating noncancerous cells into cancerous ones, to parse out which genes play which role.

More than 1,000 gene mutations are associated with colon cancer, and any given tumor has about 100 mutations, Dr. Shay said. “No two human cancers have more than a few mutations in common.”

Of those genes, 151 were considered to be “driver” genes – genes that actually caused the cancer, while the rest were incidental “passenger” genes.

“All of a sudden I put two and two together, and realized we had the cells to test this,” Dr. Shay said. The researchers tested the genes by looking at one of the “hallmark” traits of cancer cells – the ability to grow without being physically attached to a substrate. The researchers used bits of RNA, called small interfering RNA, to block the genes, simulating a mutation.

The researchers found to their surprise that of the 151 driver genes, 65 were involved in anchorage-independent growth.

When looking at another hallmark trait – the ability to migrate through the substrate they’re grown on – 22 of the 151 driver genes played a role.

The researchers are now screening the UT Southwestern collection of 200,000 compounds to search for potential drugs that can tackle these individual characteristics and the genes that control them. With the tools of interfering RNA, computer informatics, and high-throughput screening, they have high hopes of finding new therapies for cancers.

“I’m like a kid in a candy store,” Dr. Shay said. “The methodologies that have developed over the last decade are earthshaking. We can do things I only dreamed of in graduate school.”