Invasion Frontiers in Liver Metastases: From Cellular Processes to Novel Therapeutic Strategies

Metastases are the main cause of cancer mortality.

In liver metastases, prognosis depends on the histological pattern of the invasion front: Extensive tumor-hepatocyte contact is linked to inferior outcome, while a perimetastatic stromal capsule predicts favorable survival, suggesting critical differences in tumor invasion. We study the biology of metastatic invasion in mice and patient samples.

Recently, we have shown that encapsulation represents a failure of tumor cells to invade the liver plates, resulting in liver repair.

Using single-cell interaction mapping, we uncovered that active invasion induces liver injury, mounting in the exhaustion of injury-induced transdifferentiated hepatocytes towards the tumor center.Based on these data, we hypothesize that liver injury in metastases is a double-edged sword, promoting either tumor invasion or liver repair.Here, we propose generating a cell-level spatiotemporal map of the events from active via impaired invasion to encapsulation.

Using mouse models and single-cell sequencing, we will identify the cell types and signaling pathways that regulate the balance between tumor invasion and liver reparation.

Selected pathways will be confirmed in human material, followed by functional assays to target tumor invasion in vivo and in heterotypic spheroid cultures.The expected outcome is a wiring diagram of the cellular facilitators and inhibitors of metastatic invasion, ultimately leading to novel ways to inhibit metastases growth.