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I was very surprised when reading Alberts Molecular Biology of the Cell that “The Changes in Tumor Cells That Lead to Metastasis [cancer spreading through the body] Are Still Largely a Mystery”. This is my attempt at an answer, plus some thoughts on what cancer even is.

To understand cancer, I think you have to ask: why do young people get less of it? Why is cancer something that occurs at all times in most species, but is effectively only lethal to aged animals?

There are two standard answers to this: either cancer is caused by combining certain mutations (a lottery), and that just gets more likely with time (you draw a ticket every day, eventually you get unlucky), or because our immune system, which keeps cancer in check, gets weaker as we age. These two certainly play a role, but I want to propose a more fundamental theory: for cancer to spread (metastasize, which ultimately kills you) it needs to find areas where new cancer can form. Animals that don’t die from cancer (young people, naked mole rats, plants, etc.) don’t control the arising of cancer, but they effectively make it impossible for cancer to spread. The way they do this is by minimizing the phase boundaries between separate cellular communication collectives, where the goal state of the local environment (the “phase identity”) is less clearly defined. As we age, these areas increase, as intercellular signaling degrades, and we get lethal forms of cancer.

Let's unpack this hypothesis. First, what IS cancer? In the simplest worldview, cancer is just "a change in the level at which evolutionary pressure dominates". (For more on this, see the interview with Athena Aktipis on why cancer is a fundamental phenomena in our universe or her book) When I'm healthy, evolution works on me, all my cells sacrifice each other (literally. There are immune cells which throw out their DNA as nets to trap invaders, the most badass seppuku imaginable), for the greater good (me). But sometimes, cells stop sharing that goal and become rogue, selfish, individuals. Cancer is rebellion.

Now this usually doesn't pose a problem, our internal military (immune system) squashes down rebellions all the time. But more importantly, our cells talk to each other constantly, indoctrinating, controlling, checking in with their neighbors, and justifying each and every action to the collective. If any cell notices they are stepping out of line, they rather commit suicide (apoptosis) than harm the great overlord (the germline, me). This explains why, in my opinion, the most important oncogenes (a mutation that makes cancer more likely) are all related to gap junctions, see Bioelectric signaling: Reprogrammable circuits underlying embryogenesis, regeneration, and cancer: Cell. Gap junctions are connections between cells; tey allow them to exchange their cell plasma, their internals, and therefore all their inputs, beliefs, decisions, and outputs. They exchange their selves. Now if you and your partner both had perfect, constant, involuntary mind-reading, would it even make sense to talk about two different you's?

This mechanism - of sharing goals between large collections of cells through gap junctions (and exosomes) - is what keeps you alive, and rebellions at bay. But sometimes, though unfortunate accidents, cells not only acquire mutations that make them dangerous (want to spread their ideas, acquire resources, don't want to die, etc. all the classical convergent instrumental goals of misaligned optimizers), they also lose their gap junctions, their safety mechanism. You have cancer.

What happens if you get a collection of cells not wanting to be you anymore? They revert back to the single cell behavioral program, increasing growth rates (removing growth cycle check-points) evolvability (removing repair machinery), even switching to a faster, but less efficient metabolism (Warburg Effect). But your body is remarkably resilient to this. Unless the cancer occurs in a critical system like the central nervous system or the bone marrow, only 10 to 30% of solid tumors kill you without first metastasizing - essentially overwhelming the whole system. This makes the study of why cancer metastasize more often with age the most important question when it comes to solving cancer.

First, it’s important to note that cancer wants to metastasize - making backup copies of yourself is a good strategy (or rather those who don’t don’t survive).

But how could you do that, from the point of cancer? To you everything around you is a hostile environment, you’re lucky that you’ve found a survivable niche in the first place. But how do you find a new one?

This is essentially the question that all species face: how do you find new environmental niches that have the right conditions? Evolution solved came up with two solutions: taking the bus (seeds, parasites) or walking there themselves (flagella, muscles).

I don’t know if anyone has found a cancer that evolved their own motion apparatus (I could see that happen in plants or organisms without a circulatory system, which would be very fascinating). But we know a lot of cancers who just “drop their children into the wind”, aka. the blood stream.

Interestingly, even that is not enough: many cancers are dividing themselves into the bloodstream - and still there is no new cancer:

Three hypotheses offer themselves:

Given that we have found no link between genes and ability to metastasize, we can probably rule out 1. 2a has been explored widely - and led to approaches like CAR T-cell therapy. But I think 2b and 3 are the ones that will finally allow us to make significant progress when it comes to preventing metastasis.

Both of them make the case that what’s worse in older individuals is not the cancer or the immune system changing, but your self is changing. If the opposite of cancer is … you, then a changing you could be to blame.

So how do you change with age?

There happens to be a really fascinating phenomena when you couple cells (or really anything) together. If you assume just one thing, namely that the strength of a connection depends on the similarity between neighbors (what wires together fires together) you automatically get “phases”, “transitions” and “boundaries”. This is a really fundamental thing to understand: Start with a collection of connected things. Invent one property they all have in common, but with different values, like “political tribe”. Start by randomly assigning each one a value. Now let them look at their neighbor to change their position, but only have them update, if they already agree with that position: you get clusters. You get tightly coupled regions, that all have the same opinion. (you can do some math to change the average size of the region, but you’ll always get regions).

This is critical to understand for biological systems, because it turns out there is at least one such property: voltage membrane potential (think of it like how easy it is for charged particles to enter or leave a cell). $V_{mem}$, how it’s called, is influenced by gap junctions - connected cells have a similar value - but also the strength of the gap junction is determined by how similar $V_{mem}$ was in the first place. For a fascinating and highly important paper, that explores this in detail see:

But the details don’t really matter, there is probably more than bioelectricity that has this - after all, I think this is the mechanism by which multicellular organisms create compartments. If you take an undifferentiated (not yet specialized cell), it looks at its surroundings - and then specializes accordingly. But its surroundings are exactly this: a set of values that are regionally very different, but highly uniform in each and every one of them.

Now if you have phases, you also have boundaries: regions in which cellular connections are in an either-or state, undecided, confused. It requires comparatively little effort to “switch” these: if they are pushed just slightly in one direction, they fall into a new equilibrium. Think of these regions as countries with swing states: if you get only a tiny fraction of them, you get the whole.

On Cancer:

On Misalignment:

On Phase Boundaries:

In academic work, please cite this essay as:

Groß, Heye, “Metastasis can only happen at Phase Boundaries”, heye.earth (2023-11-15), available at https://heye.earth/projects/cancer-kills-only-the-confused