Researchers have identified an RNA-binding protein that played a role in colon cancer relapse, offering new insights into how cells persist in the presence of chemotherapy.

Somewhat ironically, the cells that drive relapse are able to survive chemotherapy because they are not thriving in the first place.

"The majority of these tumor cells proliferate very aggressively," Eduard Batlle told BioWorld Science. And that proliferation is what makes them vulnerable to chemotherapies, which act on dividing cells.

But there is "a subset of cells within the tumors [that] are probably not very well adapted to the environment, and that induces a latent mode that confers chemoresistance."

Batlle is a researcher at the Catalan Institution for Research and Advanced Studies (ICREA) and head of the colorectal cancer laboratory at the Institute for Research in Biomedicine Barcelona. He is the senior author of the paper describing the findings, which was published on June 30, 2022, in Nature Cancer.

Even advanced colorectal tumors typically remain sensitive to chemotherapy. But although the tumors overall shrink there are some cells that are insensitive to chemotherapy and can seed relapse. Such "persister" cells are not resistant due to mutations. Rather, it is reversible changes in gene expression that put them into a latency state, which can be reversed when conditions improve.

In their experiments, the authors used organoids to understand how tumor cells adapt to conditions in vivo by testing the effects of different culture media meant to mirror the conditions inside a tumor.

Patient-derived organoids can predict the response to chemotherapy, and there are biobanks of such organoids. In order to grow in culture, though, most of those organoids require nutrient media that are used to grow stem cells.

The team first grew mouse tumor organoids in suboptimal culture conditions. Such organoids were not only able to survive, but they developed resistance to chemotherapy.

Through RNA sequencing, the team showed that the cells became reminiscent of fetal intestinal progenitors. "Persister" cells that survived their malnutrition expressed the RNA-binding protein Mex3a.

In a further series of experiments, the team showed that by deleting Mex3a, they could restore sensitivity to chemotherapy.

Mex3a-deficient cells became less stem cell-like and more like intestinal goblet cells, which line the intestinal tract.

Batlle said that the findings are likely to apply to cancers of the gastrointestinal tract, because that is where goblet cells are found. Mex3a may also play a role outside of the gastrointestinal tract, but the cellular architecture the team observed makes this less likely, although other studies have also shown a role for Mex3a in gliomas.

Batlle said that in future work, he and his colleagues are "very much interested in understanding what genes are controlled by Mex3a."