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Control of cell migration in response to injury by the cancer-associated adhesion molecule EpCAM

Project Summary

Solid tumors often display a mode of cell invasion that resembles collective cell migration (CCM), a complex supra-cellular program that controls posterior lateral line primordium (pLLP) as well as kidney (pronephros) development during zebrafish embryogenesis. We found that cxcl12a and cxcr4b, while essential for pLLP migration, are superfluous for pronephros development. However, both epcam and cxcl12a/cxcr4b signalling are required to transiently override CCM to repair laser-induced pronephric tubule injuries. We also discovered that depletion of the transcriptional regulator myca or the tumor suppressor hic1 compromised the migratory-based repair response, and found that depletion of cmtm4 and cmtm6, two novel epcam-interacting proteins, augmented the repair defect in epcam-deficient zebrafish. We propose to use genetically modified zebrafish and mouse models to identify the molecular mechanisms that orchestrate early migratory responses after injury.

We will 1) examine the role of cmtm4 and cmtm6 in zebrafish pronephros development and repair, analyse whether the mammalian homologues control EpCAM trafficking, and determine their role after acute kidney injury in mice with an organ-specific Cmtm4/6 excision;
2) determine how hic1 controls the migratory response after injury, and examine the role of other hic1 target genes in the repair process;
3) determine the transcriptional response after laser-induced injury, using single-cell gene profiling, aiming to identify key transcriptional regulators involved in the migration-dependent repair process.

Collectively, these experiments will provide novel insight into the signalling pathways that orchestrate the repair response after injury. Since these mechanisms are closely linked and transiently override collective cell migration, the results may also help to better understand tumor invasion and provide new approaches to facilitate repair responses and/or inhibit metastasis.