04:43am Monday 18 November 2019

Understanding Misguided Gene Expression in Cancer

Identical twins do indeed start out with the exact same order of letters in their DNA sequence. But while most people attribute differences between them to the environment, they may also be due to epigenetics, a research field that “has exploded in the last 20 years,” according to Peter Lewis, an assistant professor of biomolecular chemistry affiliated with the UW Carbone Cancer Center.

If the DNA sequence spells a word in a recipe, epigenetics determines how that word is read, or interpreted, by a particular type of cell, says Lewis.

And if a misspelled word can be the first step toward uncontrolled cell growth, the hallmark of cancer, so can a misinterpreted word.

“Epigenetic pathways act behind the scenes in most types of cancer, although they don’t always play the driver role,” Lewis says. “These pathways are like a gun-for-hire: together with cell type-specific molecules, they determine if, how and when the DNA sequence is expressed, or translated into protein.”

An important part of these pathways are protein chaperones that act as molecular switches: by making DNA accessible to other proteins, they turn a gene on; by making it inaccessible, they turn it off. The mechanism behind such a switch is anything but simple.

“To get six feet of DNA into a nucleus that is a few microns in diameter, you need to package it very tightly,” Lewis explains. “The chaperones orchestrate an intricate dance in which the DNA is wrapped around a set of histone proteins, like beads on a string, and then folded into higher-order structures.”

DNA access requires the beads to be popped out and then back in again. A mutation that compromises the ability of chaperones to do this job correctly plays a key role in the rare form of pancreatic cancer that killed Apple co-founder Steve Jobs.

For other cancers, timing is everything. The result of certain histone mutations depends entirely on a cell’s age: adult cells remain unharmed, but those of a developing child are highly vulnerable.

“These types of mutations have to hit the right cell at just the right time. When they do, they are exquisitely primed to destroy the normal development of a child’s cells, resulting in pediatric brain or bone tumors,” Lewis says.

A better understanding of the cellular pathways that are misregulated in these devastating tumors opens up new possibilities to diagnose and treat them.

Antibodies that recognize aberrant histone proteins are excellent biomarkers that can guide personalized cancer treatment, especially immunotherapy – a hot research field that many oncologists are very excited about.

“Immunotherapy takes T cells, the patient’s immune system, out of the body, trains them to recognize a molecule that is only found in tumor cells, and then puts the newly trained T cells back into the body,” Lewis explains. “If we learn how to target tumors that precisely, we can avoid damaging healthy tissue, as traditional radiation and chemotherapy do.”

Lewis’ groundbreaking work has recently been recognized with the 2015 Kimmel Scholar award and the 2015 Shaw Scientist award of the Greater Milwaukee Foundation.

University of Wisconsin School of Medicine and Public Health

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