Targeting the prometastatic function of cancer-associated fibroblasts in breast cancer: the promise of inhibiting the MNK/4E signaling axis

The MNK1/2-eIF4E (MNK/4E) signaling axis is an important node of gene expression regulation in cancer cells, where it promotes selective translation of mRNAs with pro-metastatic functions.

However, the extent of its involvement in supporting the pro-tumor phenotypes of tumor-associated cells has largely been unexplored.

I have data showing that the absence of phospho-4E (p4E) specifically in mammary fibroblasts impedes breast cancer metastasis in vivo.

I propose that in the cancer-associated fibroblasts (CAFs), MNK/4E signaling favors enhanced translation of mRNAs that underpin their pro-metastatic functions.

To explore this hypothesis, I will use primary WT and p4E-deficient fibroblasts co-implanted with breast cancer models, utilizing the complementary expertise of my host laboratories at McGill University and KI to characterize, functionally and genetically, their MNK/4E-driven phenotype in the tumor microenvironment (TME).

To enhance the translational potential of my findings, I will apply imaging mass cytometry to unique material from patients treated with MNK1/2 inhibitors as a part of an ongoing clinical trial at McGill University and assess the MNK1/2 inhibitor-associated changes in the TME.

This project will be the first to define the mechanism of the pro-metastatic activity of MNK/4E in the fibroblast, a critical cancer-associated cell type, and is directly relevant to the ongoing clinical testing of MNK1/2 inhibitors in women with breast cancer.