How a complex network of proteins contributes to cancer survival
The epi-chaperome might offer new cancer vulnerabilities to target
Cancer is usually classified as a genetic disease; characterized by the fact that genomes of cancer cells are unstable, full of mutations and generally messed up.
Much of cancer research was focused on identifying what mutations occurred, and how these mutations would benefit one of the several hallmarks of cancer. It turned out that it does not take too much for a cell to go rogue, even as little as 1 or 2 mutations in key oncogenes (e.g. pro-survival kinases) or tumor suppressor genes (usually regulatory proteins) is enough.
Yet one thing that is less clear: How do cells manage to still live once some mutations came in and “screw up” the intricate balance of thousands of components that make our cellular machines work?
It was long assumed that cancer cells utilize their emergency-pathways to handle the imbalance that mutations introduce, pathways that would usually handle external threats to the cell, like heat or pressure or toxins. Proteins involved in these pathways have been known for some time, they are so called “stress-responders”, genes that get expressed upon certain exposure to stressors. One of the best investigated class of proteins of these stress-responders are so called “heat-shock proteins (HSP)”, discovered in response to exposing cells to heat.
Heat is a threat to cells because heat can mess up chemical reactions within the cell, as well as literally “melt” chemical bonds of essential components like proteins and enzymes, the functional units within a cell. In the case of proteins, scientists would speak of “denaturation”, a process where proteins lose their structural integrity (folding). Heat-shock proteins counteract this “unfolding”, by literally acting as stabilizing partners, called “chaperones”. They basically help keeping the show running.
In a recent paper published in nature, Rodina and colleagues from the Memorial Sloan Kettering Institute in New York conducted a landmark study to identify how the sum of “stress responders” would behave in cancer compared to normal, healthy tissues.
What they discovered by painstakingly analyzing a large set of tumor specimens was a surprising “re-wiring” of chaperone components from loosely interacting proteins to a stable, survival-facilitating, high-molecular-weight complex.
Imagine each chaperone component as an individual small business in a free market situation, some are bakers, plumbers, doctors, construction workers, bus drivers, everyone doing their part to keep society running. Suddenly we find ourselves at war, and all those people get enlisted to serve under the government to maximize output for the military, the only goal to facilitate survival. The baker only bakes bread for the soldiers, the plumber builds only for army facilities, the doctor is only treating soldiers and the construction worker builds weapon factories, everybody now part of the industrial-military complex. This is what the cancer cell does to its chaperone components.
More importantly, Rodina et. al. observed this behavior of cancer cells irrespective of their tissue of origin or genetic background, identifying this chaperome “re-wiring” as a wide-spread trait of cancer cells.
Any shared trade within cancer cells has enormous consequences for therapy.
Cancer cells are notorious for being incredible different from each other, there are thousands of different mutations or genetic alterations that can cause cancer, and even once we identified the mutations responsible for a particular tumor and being able to treat it, chances are that the patient will relapse because a new mutation developed along the way. It is like fighting a war by taking out one dictator at a time, well knowing that the next fascist warlord is just waiting to take over a radicalized country.
The research of Rodina and colleagues offer a new avenue in the war on cancer. Since chaperone components get “re-wired” to join the cancer’s pro-survival machinery, they suddenly provide a critical point of intervention for therapy;
Our study unveils a novel usage of the chaperome in epichaperome networks for cancer cell survival. [..]
It manifests as an enhanced physical integration of the HSP90 and HSP70 machineries, resulting in the utilization of their capacities in the tumor cell environment, and thereby also presenting a vulnerability that might possibly be exploited therapeutically with pharmacological modulators. — Rodina et. al.
Scientist call this a “cancer-specific vulnerability”, a weakness cancer cells have that normal cells do not. This makes chemotherapy against chaperone components a compelling strategy, since “healthy” cells can handle if you prevent their bakers from baking bread (they just move on to make muffins for a living), but the cancer cell’s industrial-military complex cannot. They need those bakers to make bread, or their whole industry collapses.
Finally, we are reminded that cancer is a deeply complex disease, where we have not only to consider its genetic roots and mutations from the blueprint, but also the downstream effects on protein-protein interactions.
Like a state, a cell can be run aground by a variety of bad actors or crazy individuals (=mutations) seizing power. And once the state is transformed, just getting rid of the leader (=driver mutation) won’t necessarily solve the conflict. Systematic dismantling of it’s industrial and military capacities might.
Rodina and colleague’s research provided some valuable intelligence on these pro-survival industries cancer cells utilize; let’s exploit them!
Source: Rodina et. al., Nature, 2016
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