Breast cancer metastasis: the unexpected tale of a methyltransferase regulating cytoskeleton

Nicolas Reynoird (Institute for Advanced Biosciences, U. Grenoble Alpes, France)

12 septembre 2024


Infos pratiques

12:00 - 13:00
Salle Rosalind Franklin
Professionnel de recherche
Accès mobilité réduite

Malignant types of breast cancer that don't respond to current treatments remain a significant health challenge, largely because of their tendency to spread to other parts of the body. A deeper understanding of underlying mechanisms may offer valuable insights into alternative therapies aimed at stopping the dispersion of breast cancer cells.
Our lab recently identified the protein methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis.
While SMYD2 is overexpressed in aggressive breast cancers, we noticed that it is not required for primary tumor growth. However, we found that specific SMYD2 ablation in mammary-epithelium increases mouse overall survival by blocking metastatic spread. Mechanistically, we identified that SMYD2 monomethylates a novel substrate, BCAR3, at lysine K334 in breast cancer cells. BCAR3 is a protein localized at focal adhesions and involved in cell migration and redistribution of actin fibers. Notably, we observed that methylated BCAR3 is specifically recognized by the FMNLs proteins. These actin cytoskeleton regulators are therefore recruited at the cell edges and modulate lamellipodia properties upon BCAR3 methylation. Remarkably, breast cancer cells with impaired BCAR3 methylation lose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo. SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice.

This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis.

Nicolas Reynoird is invited by Frédéric Pendino.