Neurons synapsing with tumor cells, unbelievable but true

As a neurologist, I’ve seen more than enough breast cancer metastatic to the brain.  I never, in a million years, would have though that brain neurons would be forming synapses with them, helping them grow in the process.  But that’s exactly what two papers in the current Nature prove [ Nature vol. 573 pp. 499 – 501, 526 – 531 ’19 ]

The evidence is pretty good.  There are electron micrographs of brain metastases showing breast cancer cells acting like glia, surrounding a synapse between two neurons.  There are synaptic vesicles right next to the presynaptic membrane of the neuron which is apposed to the postsynaptic neuron (that’s what a synapse is after all). They are also present in the same neuron, whose membrane is tightly apposed  to a tumor cell, which stains positive for a type of glutamic acid receptor (the NMDAR).

Breast cancer types have been subdivided by the proteins they contain and don’t contain.  A particularly nasty one, is called triple negative — lacking the estrogen receptor the progesterone receptor and the herceptin receptor. Triple negative breast cancers account for 15 – 20% of all breast cancers, and some 40% of this group will die of brain metastases.  This paper may explain why.

The paper did some work using immunodeficient mice, transplanting human triple negative breast cancer cells into the brain.  Synapses formed between the mouse neurons and the breast cancer cells.

It is known that NMDAR signaling promotes growth tumor growth in other cancer types, and that increased NMDAR expression in breast cancer cells is associated with poor prognosis.

It is incredible to think that the brain is forming synapses with metastatic tumor cells to help them grow, but that’s what must be faced.

The excellent study confined itself to breast cancer metastatic to brain, but the study of other tumors (particularly lung) is sure to follow.

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  • Ashutosh  On October 1, 2019 at 12:05 am

    Fascinating discovery, but I am curious to know why you are so surprised: after all, cancer cells are known to hijack capillaries and other tissue around them, so is it that surprising that they hijack neurons in the brain?

  • John Wayne  On October 1, 2019 at 9:23 am

    Interesting question Ash. I would guess that our current perception of the brain is that it is less hijackable than other tissues. While this discovery is certainly scary for those patients, it may lead to some insight on how to get the brain to do what we want.

  • Ashutosh  On October 1, 2019 at 11:09 am

    Agreed; I think it could say something promising about how manipulable the brain generally is. I guess one interesting question this study asks is whether we can naturally hijack the brain, the way these cancers do, for beneficial purposes.

  • luysii  On October 1, 2019 at 4:52 pm

    The same issue has two more papers on the subject (pp. 532 – 538, 539 – 545) involving similar events between neurons and the glia of a variety of brain tumors. They weren’t included in the post, because I didn’t think they as generally important. Remarkably brain tumors comprised of neurons are exceedingly rare, probably because neurons don’t divide. I never saw one. Neuroblastoma doesn’t count as they are outside the brain.

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