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Salk scientists identify factors that trigger ALT-ernative cancer cell growth

Unregulated growth in cancer is due in large part to the fact that tumor cells can rebuild the protective ends of their chromosomes. Normally, cell division halts once these structures, called telomeres, wear down. But cancer cells keep on going by deploying one of t wo strategies to reconstruct telomeres.

One strategy, which occurs in about 90% of cancers, requires increased production of a telomere-elongating enzyme called telomerase. A less understood strategy, employed by the remaining 10–15% of cancers, is called ALT (for Alternative Lengthening of Telomeres). Biologists knew ALT existed simply because tumor cells could rebuild long, albeit unkempt-looking, telomeres without telomerase, but how they did it remained a mystery.

Recently, scientists in the laboratory of Jan Karlseder, holder of the Donald and Darlene Shiley Chair, reported in Nature Structural and Molecular Biology the first experimental induction of an ALT telomere-building program in human cells.

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"People have been targeting telomerase as a potential cancer therapy for a long time," Karlseder says. "But mouse studies show that when you suppress telomerase, cells can upregulate ALT. That makes it absolutely critical to develop ways to block ALT."

To learn how cells switch on ALT, the group eliminated two proteins, ASF1a and ASF1b, in normal lung cells and in a cancer cell line that relies on telomerase for immortality. They found that ASF1-depleted cancer cells switched off telomerase but continued to thrive, meaning that tumor cells can exploit either strategy for elongating telomeres.

Most significantly, microscopy showed that nuclei of the depleted cells contained aggregates of telomeric DNA, known as PML bodies, which are a hallmark of ALT-dependent cancers.

"Massive PML body formation in normal cells was unexpected," says Roddy O'Sullivan, a postdoctoral fellow in the Karlseder lab. "It was our first clue that ASF1 loss induces ALT."

The team also found that ASF1 loss initiated an intra-nuclear ping pong game: cells replicated an embedded fluorescent tag, then tossed it back and forth between different chromosomes, building disorganized but serviceable telomeres.

"In mammalian cells we have only been able to study ALT in cells derived from ALT-dependent tumors," adds Karlseder. "Now that we have a controlled way to induce the pathway, we can test any gene that might act as an inhibitor."