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A new molecular signature to better identify radiosensitive patients

A study co-piloted by researchers from LGRK (IRCM/CEA-Jacob) and Claude Bernard Lyon 1 University and performed on cells from patients who experienced severe adverse effects after radiation therapy enabled the identification of a novel molecular signature of excessive radiosensitivity in healthy tissues. In their work, published in Frontiers in Oncology, the team showed that the NFATC2 gene contributes to cellular response to ionizing radiation and radioresistance. Their results open new vistas for studying the mechanisms involved in radiosensitivity.

Published on 3 February 2021

In radiation therapy, the term "radiosensitivity" is deployed for a number of imbricated concepts. At the cellular level, it describes the sensitivity of cells to ionizing radiation, evaluated mainly by the rate of immediate or delayed cellular death and by the cell's ability to repair DNA damage from radiation. At the organism level however, radiosensitivity describes a patient's overreaction to exposure to ionizing radiation. In most patients, therapeutic radiation doses cause no or only slight and transitory secondary effects. In others, that same dose may cause important secondary effects, including, for example, severe lesions in the non-cancerous tissues surrounding the targeted tumor. These patients are referred to as being "radiosensitive."

As many as 5 to 15% of patients undergoing radiation therapy will prove radiosensitive and experience such lesions. However, the molecular mechanisms underlying such events remain mysterious and the associations between cellular and tissular radiosensitivity are still debated.

In a new study published in Frontiers in Oncology, researchers from the Genomics and Radiobiology of Keratinopoiesis laboratory (IRCM) partnered with the SKIN team of the Tissue Biology and Therapeutic Engineering Laboratory (LBTI; UMR 5305 - Claude Bernard Lyon 1 University) to study skin fibroblasts¹ obtained from a cohort of patients who presented severe adverse effects in a range of tissues including the skin after tumor radiation therapy (RT). Their objectives were to characterize associations between cellular radiosensitivity and patient radiosensitivity (for each patient) and clarify the molecular mechanisms involved in the cell's response to ionizing radiation exposure.

They first observed that the fibroblasts of radiosensitive patients (RT-fibroblasts) where more susceptible to radiation toxicity than were fibroblasts taken from controls. This manifested as a greater rate of cell death among the RT-fibroblasts, notably due to important DNA repair defects. These initial results reinforce known relations between cellular, tissular and clinical radiosensitivity.

For the molecular aspects of their work, the researchers compared the transcriptome² of RT-fibroblasts to that of normal fibroblasts and identified 540 genes that were deregulated in the radiosensitive patients. Among those, the team focused its attention on the nuclear factor of activated T cells 2 (NFATC2) gene, which codes for a transcription factor originally described in the activation of T cells³. NFATC2 has been shown to participate in numerous cellular functions, particularly apoptosis and cell cycle regulation, but a role for it in radiosensitivity had not been reported. The IRCM-LBTI team observed very low transcript and protein expression of NFATC2 in the RT-fibroblasts compared to normal fibroblasts. A methylation analysis showed that the coding sequence of NFATC2 in RT-fibroblasts was hypermethylated, which may explain its highly diminished expression in those cells.

To shed light on the role of NFATC2 in radiosensitivity, the researchers used RNA-mediated interference to silence the gene in normal fibroblasts. Those experiments demonstrated a positive correlation between NFATC2 gene expression and fibroblast survival after irradiation. The team also showed that NFATC2 silencing led to DNA repair defects. These unprecedented results identified NFATC2 as a participant in the cell's response to ionizing radiation and the phenomenon of radioresistance, and moreover opened new vistas for studying the mechanisms underlying radiosensitivity.

The IRCM-LBTI study provides a novel molecular signature of patient radiosensitivity. It should contribute greatly to the quest for cellular and molecular strategies aimed at easing the identification of such patients and the prediction of untoward consequences of ionizing radiation on healthy tissues.

1 : Fibroblasts are the principal cells of the dermis and other connective tissues, which provide a number of functions (oxygen/nutrient diffusion, protection, etc.) to the other tissues they surround or support. Fibroblasts synthesize the extracellular matrix's macromolecules, notably collagen among other proteins and polysaccharides. They furthermore secrete a range of other molecules (cytokines, growth factors, enzymes, etc.) and play important roles in inflammation maintenance and tissue repair..

Fibrosis is a common delayed complication of radiation therapy. It results from a phenotypic change of fibroblasts into myofibroblasts that proliferate and provoke pathological extracellular matrix deposits. Fibrosis can occur in most organs and may progressively cause their failure.

2 : The term transcriptome describes the diapason of RNA resulting from genome transcription.

3 : T cells or T lymphocytes are primary actors in adaptive immunity, playing key roles in eliminating infected or abnormal (e.g., cancer) cells.

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