They discover the key to the reappearance of colon cancer after chemotherapy

About 1 in 25 people will develop colon cancer in their lifetime. In Spain alone, the annual number of new cases amounts to about 30,000. The most common medical treatment for colon cancer is chemotherapy, which is initially effective in most cases. However, many patients relapse after treatment.

Scientists have discovered the key to the recurrence of colon cancer after chemotherapy.

This research, led by Dr. Eduard Batlle, ICREA researcher and head of the Colorectal Cancer laboratory at the Barcelona Biomedical Research Institute (IRB Barcelona), reveals that some tumor cells remain in a latent state and that, after treatment with chemotherapy , are reactivated to regenerate the disease.

Specifically, scientists have discovered that tumor stem cells with Mex3a protein activity remain in a state of latency that makes them resistant to chemotherapy. Due to the action of these drugs, they adopt fetal characteristics and, some time after chemotherapy, when the environment is more favorable, they reactivate to regenerate the tumor with all its complexity. The persistent cells are responsible for the recurrence of the disease after treatment.

The cells shown in brown do not initially contribute to tumor growth (shown in the left photo) but are resistant to chemotherapy. These cells, which express the Mex3a gene, are capable of regenerating the tumor after it has been eliminated and after the treatment has finished (right photo). (Images: IRB Barcelona. CC BY-NC-ND)

“Chemotherapy is effective and kills most tumor cells, but not all. Our discovery reveals the identity of a group of persistent cells, capable of resisting chemotherapy, which will regenerate the tumor after treatment. It opens the way to being able to develop drugs to eliminate them, which would make chemotherapy much more effective and improve survival rates”, explains Dr. Batlle, also group leader at the Center for Biomedical Research in Cancer Network (CIBERONC). ) in Spain.

This study has been carried out mainly using cancerous organoids, which are small cancers derived from patients, which can be grown in the laboratory and which reproduce the complexity of the tumor in terms of its three-dimensional structure and the variability of cell types. “The organoids have allowed us to trace the evolution of the cells responsible throughout the process and observe their reaction to chemotherapy treatment,” explains Adrián Álvarez-Varela, co-author of the study.

The project has also worked with mouse models of colon cancer in which it has been possible to observe and reproduce the behavior of these persistent cells, as observed in organoids. Finally, the results obtained in organoids and mice were contrasted with the transcriptomic analysis of patient samples.

Furthermore, Dr. Batlle and his colleagues show that deletion of the Mex3a gene using genetic engineering techniques makes colon cancers highly sensitive to chemotherapy. In experimental models of colon cancer, metastases that are deficient in Mex3a are completely cured with chemotherapy. Although the functions of the Mex3a gene are still unknown, this finding suggests that drugs directed against Mex3a could act synergistically with chemotherapy and prevent recurrences.

Future work in the laboratory will focus on analyzing the underlying molecular mechanisms and, in particular, on detailing how the Mex3a gene keeps cancer stem cells in this dormant state, as well as on the study of the processes triggered by chemotherapy in these cells.

This work has been carried out in collaboration with the biostatistics and bioinformatics scientific platform, led by Dr. Camille Stephan-Otto Attolini at IRB Barcelona, ​​where they developed the computational analysis of the genetic study of the data from the mice and the patients. The group of Dr. Sabine Tejpar, at the Catholic University of Leuven in Belgium, has carried out an exhaustive search for markers in patient samples.

Researchers from the National Center for Genomic Analysis (CNAG-CRG) in Barcelona, ​​the Ludwig-Maximilian University in Munich, Germany, and the University of Palermo in Italy have also participated.

The study is titled “Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy”. And it has been published in the academic journal Nature Cancer. (Source: IRB Barcelona)