The average living cell needs communication skills: It must transmit a constant stream of messages quickly and efficiently from its outer walls to the inner nucleus, where most of the day-to-day decisions are made. But this rapid, long-distance communication system leaves itself open to mutations that can give rise to a “spam attack” that promotes cancer. Prof. Rony Seger of the Weizmann Institute’s Biological Regulation Department and his team have now proposed a method of shutting off the overflow of information before it can get to the nucleus. If the initial promising results hold up, the method could be used to treat a number of different cancers, especially several that develop resistance to current treatments, and it might possibly induce fewer side effects than those treatments do. These findings appeared today in Nature Communications.
Since cells don’t have electronic communication, they use proteins; and they generally manage to send messages quite ably, even getting them through the membranes surrounding the cells and those around the distant nucleus to which the information must ultimately be delivered. A directive from outside the cell – for example a growth factor molecule telling the cell to divide – stops at the cellular membrane. A receptor on the membrane’s outer surface accepts the message and passes its signal to the inner side. From there, “if the molecules were human messengers, they would have to transverse the equivalent of some 70 km to get from the outer membrane to the nucleus,” says Seger. Instead of sending messages all the way by a single courier molecule, the cell speeds things up with a sort of relay in which the message gets handed from one molecule to another. This whole membrane-to-nucleus communications system is known as a cellular signaling pathway, and there are about 15 different pathways for transferring the cell’s main internal messaging.
Seger has identified a number of the proteins involved in these pathways, especially in one particular pathway, called the MAPK/ERK cascade, which is involved in cancer. Dysregulation of this pathway shows up in some 85% of all cancer types. In normal cells, the messages these proteins pass along are normally delivered in spikes: The last protein in the relay slips into the cell nucleus, delivers the memo, and slips out again. But following certain mutations, the previously useful message becomes spam: It gets sent over and over, flooding the nucleus’s “inbox.” The response to this “spam attack” can be disastrous; in the case of such messages as those to grow or divide, the result may be cancerous.
Immortalized cells, left, pretreated with a drug that blocks the ERK signal, and right, without the pretreatment. Top cells are untreated, while the bottom ones are stimulated
Prof. Rony Seger’s research is supported by the Willner Family Center for Vascular Biology, which he heads; the Maurice and Vivienne Wohl Biology Endowment; the Judy and Monroe Milstein Fund for Ovarian Cancer Research; the Leah and Jack Susskind Foundation; Katy and Gary Leff, Calabasas, CA; Dr. and Mrs. Bernard E. Small, Montauk, NY; Gerhard and Hannah Bacharach, Fort Lee, NJ; Mario Fleck, Brazil; the estate of Leon Weiss; the estate of Lydia Hershkovich; and the state of John Hunter. Prof. Seger is the incumbent Yale S. Lewine & Ella Miller Lewine Professorial Chair for Cancer Research.
Weizmann Institute of Science