11:42am Saturday 21 October 2017

Enzyme Discovered at Weill Cornell Suggests New Way to Target the Spread of Cancer

The finding provides new opportunities to prevent cancer metastasis and helps explain how one drug that is already in development works to stop the disease’s spread.

The SRF pathway is known to be important for the invasion of cancer cells into normal tissue — the process of cancer spread and metastasis. This image shows how MICAL-2 reorganizes actin in the nucleus, which leads to the activation of the SRF transcription factor.

The pathway, described in the Jan. 16 online edition of Cell, centers on a protein known as serum response factor (SRF). SRF is a transcription factor, meaning that it binds to specific DNA sequences and controls the expression of messenger RNA in a process known as transcription. The protein plays a critical role in the life cycle of cells, regulating their growth and controlling their ability to migrate through tissue, a critical step in the process of metastasis.

Investigators in the laboratory of senior author Dr. Samie Jaffrey, a professor of pharmacology, discovered that an enzyme known as MICAL-2 is necessary for SRF to function in cells. Dr. Mark Lundquist, a postdoctoral associate in Dr. Jaffrey’s lab, found that cells expressing MICAL-2 resembled cancer cells in their shape and high growth rate. (Unregulated cell growth is the fundamental cause of cancer.) When Dr. Lundquist examined these cells, he found that SRF had become overactive. MICAL-2, it turned out, triggered the activity of SRF, reprogramming the transcription in the cells to resemble that seen in metastatic cells.

“One of the things we’re finding that we’re really excited by is that there are many cancers, especially metastatic cancers that have the poorest prognosis, that also have very high levels of MICAL-2,” Dr. Jaffrey said. “We think that this upregulation of MICAL-2 is causing them to be metastatic.”

When Dr. Jaffrey’s lab did an analysis of genetic data from a number of different cancer types, they found that many of the most deadly tumors had high levels of MICAL-2. These cancers were also much more likely to spread to other parts of the body, which supports the idea that MICAL-2 may act as a switch that causes cancer cells to metastasize.

Because of their structure, enzymes like MICAL-2 are typically good targets for drug therapies. While the Weill Cornell scientists were investigating the role of MICAL-2 in the SRF signaling pathway, they realized that colleagues at the University of Michigan were developing a new drug that stopped cancer cell metastasis, though the Michigan investigators did not know how their drug worked. Working with these investigators, who are co-authors on the Cell paper, Dr. Jaffrey’s team demonstrated that the new drug, known as CCG-1423, worked by blocking MICAL-2.

The finding is important because it shows that MICAL-2 is a viable drug target and that if it is blocked, cancer metastasis can be halted.

“We now know that drugs that target MICAL-2 exhibit beneficial effects in preclinical tests of metastasis,” Dr. Jaffrey said.

Ultimately, unlocking the role of MICAL-2 may open the door to an entirely new kind of metastatic cancer drug.

“Now we have a path to improving CCG-1423 and getting highly potent, highly selective MICAL-2 inhibitors, which would be a completely new class of compounds for targeting metastasis,” Dr. Jaffrey said.

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