Tumor plasticity

Tumor cell plasticity is a key property enabling certain tumor cells to adapt to diverse microenvironments, thereby facilitating their metastatic spread. In epithelial tumors, plasticity most frequently associates with phenotypic changes distributed along an epithelial-mesenchymal differentiation axis. Over the years, the team has contributed to show that epithelial-mesenchymal transitions (EMTs) generate hybrid cells with enhanced metastatic potential, (i.e.  metastasis precursors or metastasis initiating cells). (Francart et al., 2018; Genna et al., 2020).

Current research

Our research has more particularly bridged EMT to coagulation. In fact, hypercoagulability is a long-known correlate of malignancy and thromboembolism, a recognized leading cause of cancer-related death. Thus, studying molecular mechanisms underlying EMT-associated metastatic potential, we have demonstrated that EMTs induce the expression of Tissue Factor (TF), the major cell-associated initiator of the coagulation cascade, thereby providing EMT-derived tumor cells with enhanced coagulant properties and metastatic abilities. TF-mediated procoagulant properties indeed contribute to the generation of a pericellular fibrin/platelet-rich cocoon that may protect Circulating Tumor Cells (CTCs) in the blood stream, and also provides a provisional matrix for metastatic niching. At a molecular level, we identified several EMT-associated mechanisms that converge to upregulate TF expression. EMT transcription factors snail and ZEB1, and the stem cells marker CD44 were found to regulate TF at the transcriptional level. We also identified a novel mechanism by which vimentin interferes with a miR-dependent negative regulation of TF mRNA, thereby promoting coagulant activity and early metastasis of vimentin-expressing CTCs

In collaboration with Prof. Guy Jerusalem and Dr. Hélène Schroeder (oncology department of the CHU Sart-Tilman), we are also exploring this EMT/CTC/coagulation axis in cancer patients. We were thus able to correlate TF expression to vimentin expression in Triple Negative Breast Cancer patients, and to identify a subpopulation of CTCs co-expressing vimentin and TF in metastatic breast cancer patients.

Objectives

• deepening our molecular comprehension of TF-mediated metastasis (coagulation-dependent and independent mechanisms)
• identifying targetable EMT-driven regulatory pathways of TF expression, in order to hinder TF-mediated mechanisms of metastasis
• engineering 3D-cell models of metastatic niches to decipher niching mechanisms of EMT+ CTCs
• developing a µfluidic assay to characterize human coagulant CTCs (collaboration with Pr. Tristan Gilet, Microfluidics Lab and Dr. Stéphanie van Loo, LiveDrop).

Bourcy et al., Cancer Res., 76 (14):4270-82, 2016. doi: 10.1158/0008-5472.CAN-15-2263.

Francart et al., Dev. Dyn., 247(3):432-450, 2018. doi: 10.1002/dvdy.24506.

Genna et al., Cancers, 12(6):1632, 2020. doi: 10.3390/cancers12061632

Francart et al., Oncogene, 39:3680–3692, 2020. doi: 10.1038/s41388-020-1244-1

Villard et al., Cancers, 14(13):3288, 2022. doi: 10.3390/cancers14133288.