What if acting on the cells surrounding the tumour could improve the effectiveness of treatments? On 14 September 2022, a team from the SIRIC ILIAD specialising in breast cancer published a scientific article along these lines.
Breast cancer is the most common cancer in women and the leading cause of cancer deaths1. In recent years, with screening in particular, the prognosis for some subtypes of breast cancer has improved. However, this is not the case for the most aggressive subtypes, which are resistant to current treatments and require new therapeutic alternatives.
Surrounding cells: the allies of cancer cells
An organ in general, including the breast, is composed of many different cells, including epithelial cells – which become cancerous in breast cancer – and supporting cells, including fibroblasts.
« In breast cancer, fibroblasts are the major component of the tumour. They can make up to 70% of the tumour mass. » Frédérique Souazé, INSERM research fellow
Cancer cells are not isolated, but interact with neighbouring or surrounding cells. They change their environment and activate fibroblasts, which are therefore called “cancer-associated fibroblasts” or simply CAFs. There are several types of CAFs, including myofibroblasts, which help cancer cells to grow and participate in tumour progression.
Epithelial cells: Specialised cells that make up the epithelium (the layer of tissue that covers the external surfaces – skin and mucous membranes of orifices – and internal surfaces – digestive tract and glands – of the body). In the case of the breast, these are the mammary glands.
MCL-1: the survival tool for cancer cells and CAFs
The SIRIC ILIAD research team has previously shown that CAFs strengthen cancer cells by influencing their survival system. To escape cell death induced by treatments or the immune system, cancer cells have factors at their disposal. It is by increasing the presence of one of them, MCL-1, in cancer cells that CAFs contribute to treatment resistance. However, cancer cells are not the only ones to express this factor:
« CAFs also express MCL-1, which promotes their own survival and that of the cancer cells. » Frédérique Souazé
Research teams of the SIRIC ILIAD have been interested more specifically in the roles of MCL-1 in fibroblasts associated with breast cancer and their impact on the resistance of cancer cells to treatments. These research teams, attached to the CRCI²NA and the Institut de Cancérologie de l’Ouest (ICO), are the only teams in the world working on the role of MCL-1 in CAFs. The results of their work were published in a scientific article on 14 September 2022 in the journal Cell Death & Disease.
Destroy the CAFs …
« Previous studies have shown that the more CAFs there are, the worse the prognosis of the disease » Frédérique Souazé
The researchers’ first hypothesis was to destroy the CAFs and the tumour cells, using an antagonist of MCL-1, a molecule that prevents the action of MCL-1. Surprisingly, this antagonist had little effect on the death of CAFs.
Antagonist: A molecule that blocks or reduces the physiological effect of another molecule.
… Or make them allies?27
However, even if the CAFs were not destroyed, they were “deactivated”, or more simply: they lost their ability to help the cancer cells.
« In reality, the important thing is not to destroy the CAFs, but to deactivate them or prevent their activation, to break the dialogue with the cancer cells. » Frédérique Souazé
These results show an unexpected role for MCL-1 in the activation of CAFs and their function in supporting cancer cells. The next step for the SIRIC ILIAD research team will be to better understand how MCL-1 manages to modify and “activate” fibroblasts.
Ultimately, the challenge of this research is to improve the response to treatment by considering breast cancer not as a cluster of cancer cells, but as an ecosystem on which we can act.
Thanks to Frédérique Souazé and Chloé Lefebvre for their help in writing this article and a big congratulations to all the research teams: :
- Thomas Bonneaud, Chloé Lefebvre, Lisa Nocquet & Hugo Weber, PhD students and students at the CRCI²NA
- Agnès Basseville, Researcher at the ICO
- Julie Roul, ICO technician assigned to research at the CRCI²NA
- Mario Campone, University Professor, Hospital Practitioner and Director of the ICO
- Philippe Juin, Researcher and Director of CRCI²NA
- Frédérique Souazé, Researcher at CRCI²NA
To read the scientific publication: https://www.nature.com/articles/s41419-022-05214-9
1Santé publique France – http://www.santepubliquefrance.fr/
²Institut National du Cancer – http://www.e-cancer.fr/
