July 6, 2020

The Niche

Knoepfler lab stem cell blog

Probing Nature pub’s puzzling claim of brain cells globetrotting into prostate tumors

Mauffrey Nature Prostate Neural invasion 2019 Fig 3ce
Mauffrey, et al., Nature 2019 Fig 3c-e. Yellow cells are reported to be brain neural cells invading prostate tumor.

A new Nature paper makes the striking claim that neural precursor cells of the brain migrate all the way to prostate tumors. Furthermore, the team led by Claire Magnon claims that these long-distance cellular travelers from the brain not only take up residence in the prostate but also strongly drive progression of the prostate cancer via neurogenesis there.

From what I know, this claim goes counter to general principles of animal physiology so if it’s accurate, it’s a huge deal. Other than blood cells, most cells in certain tissues don’t just wander far off to other distant tissues even in disease states. Still, in science we need to challenge general assumptions and cells do sometimes wander.

The paper, Mauffrey, et al., entitled “Progenitors from the central nervous system drive neurogenesis in cancer”, is mostly based on a mouse model of prostate cancer. The tumors are driven in these mice by exogenous Myc, although the team also analyzed some human prostate tumor samples in correlative work.

The claim of neural precursors globe-trotting from the brain to prostate is not addressed in the human context, but the authors seem to think it also occurs there. Since most of the paper is on mice, we need to invoke #inmice here somewhat. If true in humans too, this is an even bigger discovery.

As a Myc, cancer, and stem cell researcher, this paper caught my attention. I also am a prostate cancer survivor myself.

I’m somewhat skeptical of the claims here and I think that the authors went out on a limb with how strongly they made their claims. In particular I strongly doubt that this occurs as part of the normal disease process in human prostate cancer development. It’s not that I see any technical red flags on first glance in the pub, but rather the core claim just doesn’t make sense to me. Of course, that doesn’t mean it’s wrong, but I’m surprised it hasn’t made more press.

So what’s going on here?

The paper largely relies on the assumption that a marker of central nervous system (CNS) precursor cells called DCX definitively marks only these CNS cells. Thus, when the authors see DCX+ cells inside prostate cancers (which is convincing), they claim that they must come from brain. However, for me a much simpler explanation is that instead local cells take on a DCX+ fate or perhaps a few already have it such as in a prostatic nerve fiber (note that DCX+ cells are found in the peripheral nervous system too) and are attracted into the tumor locally. I don’t know that the paper rules out these simpler possibilities so that’s a concern.

Even so, let’s say the paper is right that the prostatic tumor DCX+ cells are from the brain, how would brain cells get all the way from the brain to the prostate? That’s like going from Earth to the Moon, in cellular terms. The authors can detect a few DCX+ cells in the blood of their prostate cancer mice, but not many. Still, they argue that the cells go through the blood-brain barrier (on its own, a big hurdle) and then all the way from brain to prostate cancer in the vasculature. That’s possible, but surprising.

If this does happen in people, when do the brain precursor cells go to the prostate relative to the tumor initiation and growth? If the brain cells go there prior to tumor initiation, then why do they even go there in the first place? If as seems more likely they go later, perhaps attracted by the tumor, how do they contribute to the progression of the already existing tumor? The authors argue the brain cells definitely contribute to the tumor’s progression. They also suggest brain cells go to other kinds of tumors, at least in mice.

This is one of those papers that strongly shakes things up. I saw an accompanying News & Views piece focused on it, but unfortunately it doesn’t really discuss limitations of the work or ask probing questions.

In a way, I hope I’m wrong in being so skeptical. The new finding, if replicated and more definitively proven, would be very cool and I like it when there are paradigm-challenging or breaking discoveries. Still, for me at least, it’s going to take a lot more proof to be convinced.

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