ular Waste BY GARTH SUNDEM
“A common lab technique is to treat cells with what’s called the IC50 of a drug—the drug concentration at which half of the cells should die and half should survive,” says Andrew Thorburn, PhD, deputy director at CU Cancer Center, and one of the world’s leading experts on this paradox of autophagy. “Now, cancer scientists have traditionally thought of this stochastically—that is, at this concentration, it’s chance that 50 percent of cells live while 50 percent of cells die. What our work is showing is that this cell death and survival might not be chance at all. Which cells live and which cells die when faced with an anti-cancer drug may be determined in part, or even in large part, by autophagy,” Thorburn says. But, again, it’s not as simple as squelching autophagy to nix cancer cells’ protection. Take this recent finding from CU postdoc Jacob Gump, working in the Thorburn Lab: Imagine you have dishes of cells, some with high autophagy and some with low autophagy, and then you hit these cells with two drugs known to activate the machinery that leads to cell death. Gump found that with one drug (abbreviated TRAIL), cancer cells were protected by autophagy, but with the other drug (called Fas ligand), autophagy sensitized cells to the drug. But what if we were able to manipulate autophagy and patients on one drug would benefit while patients on the other drug would not? “If this finding applies in human contexts, decreasing autophagy could make a cancer cell you’re trying to kill more or less resistant to whatever you’re using to try to kill it,” Thorburn says. So which cells are which? What cancers are hurt, helped or indifferent to autophagy? Working in Thorburn’s lab, Paola Maycotte, PhD, postdoctoral researcher, has one important answer.
PATRICK CAMPBELL
TH E PROM I S E
AUTO P HAGY I N TR I P LE - N E GATI V E B R EAST CAN C E R “Sometimes with cells, the answer comes from trying new techniques on many cell lines, noticing what works, and then working to discover why the technique worked,” Maycotte says. In this case, Maycotte and colleagues gathered a panel of breast cancer cell lines, turned off autophagy in these cells, and watched closely. “One wonderful thing about working in the system of an academic medical and research center is that we have access to these important cells for our experiments,” Maycotte says, crediting CU Cancer Center’s Tissue Culture Shared Resource for providing the cell panel. After knocking down autophagy in these many kinds of breast cancer cells, Maycotte found a striking result: Nixing autophagy made chemotherapy drugs more effective in all cell lines tested, but even more striking was the result specifically in triple-negative breast cancers—the most dangerous form of the disease that is still without a targeted treatment.
Andrew Thorburn, PhD, deputy director at CU Cancer Center, is one of the world’s leading experts on this paradox of autophagy.
5 C3: SPRING 2014