i3S researchers have identified a mechanism that favors tumor growth and resistance to chemotherapy, using animal models and mini-tumors from patients.
A team from the Institute for Research and Innovation in Health (i3S) at the University of Porto has identified a mechanism that helps explain how colorectal cancer grows and resists chemotherapy. The discovery, published in the journal Cellular and Molecular Gastroenterology and Hepatologypoints to a new therapeutic target that could, in the future, contribute to making treatments more effective.
At the center of the study is the MEX3A protein, known for regulating the way cells use the information contained in messenger RNA to define which proteins are produced and how they behave. Under normal conditions, this protein has the important function of helping, in the intestine, to preserve intestinal stem cells, essential for tissue renewal.
The problem, the investigation points out, arises when this mechanism is taken advantage of by tumor cells. According to scientists, in around 85% of the tumors analyzed the protein is increased, which contributes to cancer cells having a greater capacity for growth.
The team also discovered that MEX3A reduces the activity of another protein, PPARgamma, which normally promotes cell differentiation and works as a kind of brake on tumor growth.“We found a clear inverse relationship: high levels of MEX3A are associated with low levels of PPARgamma, creating favorable conditions for tumor growth”explains Ana Rita Silva, first author of the work.
To test this mechanism, researchers turned to animal models and tumoroids, which are “mini-tumors” grown in the laboratory from patient samples. These models are part of a biobank established at i3S in collaboration with IPO-Porto and allow studying tumor behavior closer to clinical reality.
The results showed that when MEX3A is reduced, tumors become smaller and cells begin to have a less stem-like profile.But the most relevant discovery for therapeutics is the response to chemotherapy, since by decreasing MEX3A, tumor cells became more sensitive to treatments used in colorectal cancer..
“When MEX3A expression was blocked using genome editing tools, tumoroids became significantly more sensitive to colorectal cancer treatment [com quimioterapia]”, explains Bruno Pereira, senior author of the work.
The discovery suggests thatBlocking this protein could prove to be a complementary strategy to existing therapies, increasing the effectiveness of chemotherapyin patients whose tumors have high levels of MEX3A. Still, it is a line of research that requires new studies before it can reach clinical practice.
“Our results show that MEX3A not only promotes tumor 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.
The work was carried out in Portuguese institutions and involves three generations of biologists trained at the Faculty of Sciences of the University of Porto: Ana Rita Silva, doctoral candidate and first author of the study, Bruno Pereira, assistant researcher and senior author, and Raquel Almeida, leader of the research group and co-author of the work.
