The Department of Biomedicine

CCBIO seminar: Jean Paul Thiery

Epithelial cell plasticity in carcinoma: Harnessing mechanisms controlling biomechanics and progression of malignancy for the design of new therapeutic strategies

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Jean Paul Thiery
Centre for Cancer Biomarkers (CCBIO), University of Bergen, Yong Loo Lin School of Medicine, National University of Singapore, University of Paris Denis Diderot and Comprehensive Cancer Center, Institut Gustave Roussy, Villejuif, France

Epithelial-Mesenchymal Transition (EMT) is a fundamental mechanism governing morphogenesis that employs multiple signaling pathways to shape the embryo. The intriguing possibility that similar mechanisms operate in carcinoma has been documented repeatedly in experimental models, with the discovery of mesenchymal phenotypes in tumor subsets. The transition from an epithelial carcinoma to a mesenchymal-like state is potentially associated with increased stemness, therapeutic resistance, and immune escape.

EMT is executed in part through the modulation of intercellular adhesion machinery. I will present recent data on adhesive mechanisms involved in the maintenance of an epithelial state versus the transition to a mesenchymal-like phenotype.

I will then present a number of studies in support of the concept that EMT contributes to tumor progression. Our laboratory has established a universal EMT scoring system based on expression profiling. I will describe our results for the EMT spectrum of a large collection of human tumors and cell lines and emphasize the broad distribution of scores measured in distinct tumor histotypes and their corresponding cell lines. We also previously designed a high-content screening assay using a bladder carcinoma cell line that is able to undergo EMT following exposure to growth factors. This model allows us to simultaneously analyze both cell growth and cell migration using time-course imaging in multi-well plates. Using this assay, we have validated several compounds as viable EMT inhibitors. I will discuss the need for inhibiting cooperating signaling pathways in mesenchymal-like bladder carcinoma lines to abrogate their invasive properties in vivo. I will also discuss the contribution of EMT to immune avoidance using an MCF7 breast cancer cell model system, and show that MCF7 cells rendered mesenchymal-like by the forced expression of the transcription factor Snail or by a chronic TNF-α exposure become refractory to a specific cytotoxic T lymphocyte (CTL) clone. This CTL clone forms a functional immune synapse with wild-type MCF7 cells in contrast to the ‘EMTed’ or transitioned cells, which acquire a drastically modified cortical actin cytoskeleton. We have recently developed a 3D screening method to interfere with EMT triggered by endothelial cells that are organized as a vessel in a microfluidic device. This system delivers a more accurate representation of the in vivo situation. We also have analyzed the role of polarized macrophages in promoting carcinoma cell dissemination. Finally, I will explore the importance of EMT in the genesis of circulating tumor cells (CTCs). We have explored the phenotype of CTCs in vitro following their expansion in short-term culture and found that numerous CTCs express EMT markers. I will describe how these findings are consistent with other reports, and discuss how the potential for CTCs to transiently expand in vitro may be used as a surrogate marker for ascertaining patient responses to neoadjuvant therapy.

Chairperson: James B. Lorens, CCBIO