Toppling the Pillars of Cancer Cell Biology

by Caitrin Crudden, PhD candidate at the Karolinka Institutet, Stockholm, Sweden.

Caitrin in the lab

Caitrin in the lab

Picture an expansive galaxy in your head. A vast space with thousands of twinkling dots.
As seconds pass, connections flash from dot to dot – fast enough to disappear before you can even focus on one – generating an intricate, pulsating web.

I’m not a cosmologist. I’m a cancer cell biologist, and I study subcellular signalling. You probably already know that cancer is a disease of uncontrolled cell growth. But cancer cells have not gained an alien skill in order to do so; they use the exact same growth signalling pathways that every other one of your cells uses. In a cancer cell, relatively small tweaks occur in normal signalling pathways, which render them dysfunctional, often hyperactive. But the galaxy-like expansive and pulsating web of communication imagery goes part way in describing the system we are dealing with. Subcellular signalling is vast and mind-numbingly complicated, and in all of the decades of molecular biology so far, we are still piecing links together with every additional study.

But a galaxy-like network, somewhat like the task, is quite overwhelming and daunting. For simplicity, let’s imagine one signalling pathway in isolation, a bit like a chain of children in the school playground, playing a game of whispers. A message is passed from one child to the next child down the line, but instead of the usual hilarity of miscommunication, our hypothetical game is pretty exact. An un-fun version of playground whispers, if you will. Much like those children in the playground, in a cell, a message is passed from one part of the cell to another by sequential messenger molecules. For example, a message can be sent around the body in the blood in the form of a molecule. This molecular message binds to a receptor that sits on the surface of a cell prised waiting for this exact signal. The binding of the molecular message to this receptor flicks it from off to on. An on receptor turns on a nearby molecule, this on molecule turns the next molecule on, and so on and so forth, until the message is passed to the nucleus. Here, it tells the cell which genes are to be transcribed, in order to build proteins to accomplish a specific cellular task. In cancer, one or more of these signalling pathways stops working correctly because of a genetic mutation in a messenger molecule. To continue the metaphor, basically a child in the middle of chain decides to go a bit rogue.

Cell Signalling

Cell signalling

Let’s take an example. There’s a proliferative signalling pathway called the mitogen activated protein kinase pathway or simply MAPK to its friends. In the middle of it is a molecule called Ras. Normally, this pathway fires a nice concise signal in response to a message from somewhere else in the body, that tells this cell that it needs to grow and divide into two daughter cells. Maybe, for instance, the human overlord has acquired a pesky paper cut and the cells need to grow to close the wound. In that case, the message binds to a receptor on the cell, a growth factor receptor, which communicates to Ras, and Ras turns on to communicate the signal to the next molecule, which passes on to the next, and down and down a chain of messenger molecules into the nucleus, which initiates the steps that need to take place for the cell to divide. In this normal efficient situation, Ras returns to its off state as soon as it has efficiently passed its signal onto the next molecule, and in doing so, ensures a safe and distinct message is given. A successful game of un-fun playground-whispers, and everyone can pat themselves on the back and go about their day.

A common mutational event in cancer is that Ras picks up a genetic mutation that means it becomes stuck in the on position. We call this constitutive activation, which basically just means stuck-in-the-on-position. With Ras constantly on, the signal is continuously fired from it to the next molecule, even in instances when it is inappropriate for the cell to divide. Hence, these cells acquire uncontrolled growth, outgrow their neighbours and can continue to mutate and grow and move and invade and…I think you all know how this story ends.

So the answer seems logistically simple – turn Ras off, right? However, frustratingly Ras turns out to be a pretty much un-druggable molecule. Despite huge effort, the 3D surface of the protein doesn’t have pockets in which a potential drug could bind and correct it. However, efforts have been more successful in drugging its next-in-line messenger molecule, Raf. If, in our hypothetical chain of school children playing whispers, there’s one mischievous kid in the middle adding rubbish in willy-nilly, that didn’t come from anyone before her, the damage is minimized if the next partner in line simply doesn’t pass the nonsense on. Raf inhibitors showed great promise in pre-clinical development, and in clinical trials of metastatic melanoma, a truly horrible aggressive disease. Things started to look up.

Until – Bam! The drugs stop working. In a patient who initially responded well, the disease comes back – and it’s more aggressive then ever. A heart-breaking yet frustratingly common scenario. The cell is a highly dynamic system with a lot of inter-connected pathways that can flip back and forth when needed, and a cancer cell, because of its unstable genome that is prone to mutations, is even more adaptable. You can put a road block in the signal chain – Ras’s whisper-partner keeps quiet, but cunning Ras simply finds another buddy in the playground to blurt rubbish to, aaand we’re back to square one. As useful to our understanding as chain-schemes are, the network-like galaxy, in all of its sobering complexity, is more realistic. You can start to get an idea of the difficulty of treating this disease.

So, what now? Some of my current work, and that of others, is trying to optimize multi-target approaches. If a cell can circumvent the Raf or similar inhibitor road-blocks quite rapidly, we must simultaneously or synchronously take away its back up options, in a highly choreographed bank and forth dance to the death. The idea is that a multi-target network approach, which removes back-door options, minimizes adaptation of cancer cells to inhibitors and hence drug resistance. The hope is that if we design smart enough multi-target approaches, we might just be able to topple the pillars of survival that these cells rely on.

Max Delbrück, a 20th century geneticist wrote;

“Any living cell carries within it the experiences of a billion years experimentation by its ancestors. You cannot expect to explain so wise an old bird in a few simple words.”

Nor can you outsmart it, with simple strategies.


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