Mechanical stress causes nuclear and functional changes in migrating leukaemia cells

A study carried out by Dr. Javier Redondo Muñoz’s group at the Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC) could help understand how the changes and mutations suffered by leukemia cells as they migrate through the body can affect their response to conventional therapeutic treatments. The research has been published in the Cellular and Molecular Life Sciences journal.

Acute lymphoblastic leukemia is the most common pediatric cancer. Although its survival rate is high, some cell subtypes may emerge during the progression of the disease favouring the occurrence of treatment resistance and risk of relapse. The reason for that lies in the migration of tumor cells through the body. When migrating through the tissues, tumor cells cross a multitude of physical barriers which generate mechanical stress as the cells are forced to deform. Although it is known that cells respond quickly to this kind of mechanical stress, the long-term changes they undergo are still unknown.

Identifying factors that can increase the occurrence of changes in tumor cells favoring them over the healthy ones is still a great challenge in cancer research. Now, scientists from Dr. Redondo Muñoz's group have managed to identify how the persistent migration of these cells causes some permanent changes.

The results show that when cells suffer repetitive mechanical stress due to migration, the morphology and organization of their nuclei undergo some changes. Specifically, alterations in the arrangement of the nuclear protein lamin B1 and an increase in basal levels of DNA damage have been observed. Thus, cells that have been subjected to this mechanical stress behave differently and show defects in their ability to move or undergo changes in their responses to mechanical stimuli.

The authors found that these changes are modulated by cytoskeletal proteins, which are responsible for giving stability and shape to the cell. While the leukemic cell moves, specific cytoskeletal proteins transfer external mechanical signals to the nucleus, altering genetic transcription. The study suggests that the nuclear changes occurring in leukemia cells when they move could favor DNA instability and the appearance of cell subtypes that reduce the effectiveness of cancer treatment.

This research combines a cellular and molecular biology approach with biomechanical characterization and transcriptional study of cells subjected to mechanical stress.

The work is part of the CSIC Connection Cancer network. It has been carried out in collaboration with research groups from the Complutense University of Madrid and the University of the Basque Country, as well as funding from the State Research Agency, the Autonomous Community of Madrid, and several foundations such as BBVA, FERO, and AECC.

Reference: Mechanical stress confers nuclear and functional changes in derived leukemia cells from persistent confined migration. A. de Lope-Planelles, R. González-Novo, E. Madrazo, G. Peralta Carrero, M.P. Cruz Rodríguez, H. Zamora-Carreras, V. Torrano, H. López-Menéndez, P. Roda-Navarro, F. Monroy, J. Redondo-Muñoz. Cellular and Molecular Life Sciences. https://link.springer.com/article/10.1007/s00018-023-04968-5.