i3S paves the way for more effective treatments for colorectal cancer
A team of researchers from the Institute for Research and Innovation in Health (i3S) at the University of Porto has discovered a mechanism that helps explain how colorectal cancer grows and resists chemotherapy. The discovery points to a new therapeutic target that could make treatments more effective.
The study, published in the journal Cellular and Molecular Gastroenterology and Hepatology, focuses on the MEX3A protein, which controls how cells use the information contained in messenger RNA (mRNA) to determine which proteins are produced and how the cells behave. Under normal conditions, MEX3A helps to preserve intestinal stem cells, which are responsible for the renewal of the intestine.
However, the researchers found that, in the context of cancer, this mechanism is ‘hijacked’ by tumour cells. In around 85% of the tumours analysed, MEX3A levels are elevated, helping cancer cells to retain stem-like or more undifferentiated characteristics.
At the same time, the team discovered that MEX3A reduces the activity of another protein called PPARgamma, which normally induces cell differentiation, acting as a brake on tumour growth. “We found a clear inverse relationship: high levels of MEX3A are associated with low levels of PPARgamma, creating conditions favourable to tumour growth,” explains Ana Rita Silva, the study’s first author.
Using animal models and tumoroids — ‘mini-tumours’ grown in the laboratory from patient samples, which form part of a biobank established at i3S in collaboration with IPO-Porto — the researchers demonstrated that, by reducing MEX3A, the tumours shrink and the cells take on a less stem-cell-like profile.
Furthermore, the reduction in MEX3A made the tumour cells more sensitive to chemotherapy, suggesting that blocking this protein may enhance the effectiveness of existing treatments. “When MEX3A expression was blocked using genome-editing tools, the tumoroids became significantly more sensitive to treatment with 5-fluorouracil and oxaliplatin (FOLFOX), the standard chemotherapy combination used in the treatment of colorectal cancer,” explains Bruno Pereira, senior author of the study.
“Our findings show that MEX3A not only promotes tumour growth but also influences the response to treatment. This makes it a particularly relevant target for the development of future therapeutic approaches,” adds Raquel Almeida, leader of the Differentiation and Cancer group at i3S.
This research was carried out at Portuguese institutions and involved three generations of biologists from the Faculty of Sciences at the University of Porto (FCUP): Ana Rita Silva, a PhD student and the paper’s first author; Bruno Pereira, a research assistant and the paper’s senior author; and Raquel Almeida, the research group leader and a co-author of the paper.
