A team from the Salk Institute in La Jolla led by Inder Verma has reported dedifferentiation in a paper in Science some important findings that I believe make their paper in the top 10 as a candidate for paper of the year.
The paper, entitled “Dedifferentiation of Neurons and Astrocytes by Oncogenes Can Induce Gliomas in Mice” makes striking findings.
The authors show that mature neurons and astrocytes (incredibly specialized, “terminally differentiated” cells) can be dedifferentiated. This is groundbreaking because these types of cells, especially the mature neurons, were thought to be really fixed in their fate and hence possessing much plasticity. Note that dedifferentiation is sometimes called “direct reprogramming.”
The dedifferentiated cells could also lead to formation of malignant brain tumors called gliomas. Interestingly, the glioma cells exhibited many hallmarks of stem cells.
An important open question is whether the neurons are dedifferentiated first as a discrete step back to a neural stem cell or even more primitive stem cell state, which then acts like a cancer stem cell or if partial dedifferentiation is enough to kick start the tumorigenic process. In this regard, the authors state:
We propose that the genetically altered differentiated cell acquires the capacity to dedifferentiate to a more progenitor (stem cell) state, and that tumor progression probably requires a permissive microenvironment composed of cell types and molecular signals that can sustain both differentiation of tumor cells as well as maintenance of tumor stem-like cells.
Another key open question is whether these events that occur in mice also happen during brain tumor formation in people. I suspect that they do.
To trigger the dedifferentiation, the authors used a single lentiviral vector to produce virus injected into the mouse brain. They write:
…we have expanded the utility of our lentiviral system by generating a new construct that carries two shRNAs: one targeting neurofibromatosis type I gene (NF1: mutated in 18% of GBMs) and the other one targeting p53 (mutated in over 35% of GBMs)…
A picture of this vector from the paper is below.
In a The Scientist article on the paper, Verma is quoted as follows:
“What we’re saying is, any cell in the brain that gets an oncogenic insult has the ability to dedifferentiate [and form tumors],” said Verma. This might seem a rather bleak outlook, but “by knowing the mechanism, we at least have a handle to start thinking about [treatments],” Verma said.
I agree that knowing the mechanism is key here and is actually encouraging. It is difficult to fight diseases that we do not understand. I believe this paper is a major advance for the cancer and stem cell fields.
By way of a 2020 update on the lead scientist of this paper, Inder Verma, he has left the Salk related to sexual harassment allegations there.