Life, Death, and Resurrection at the Cellular Level
My laboratory studies the formation and maintenance of normal adult tissues. We investigate mechanisms of stem cell maintenance, cell fate specification, cell differentiation, morphogenesis, survival, and migration. Cell migrations are essential for normal development, wound healing, angiogenesis, and tumor metastasis. Cell migration research has focused primarily on individual cells mi- grating on extracellular matrix. However in vivo, cell migrations are diverse. Many cells migrate in interconnected groups and they can move on, or in between, other cells. E-cadherin is a major homophilic cell-cell adhesion molecule that inhibits motility of individual cells on matrix. However its contribution to migration of cells through cell-rich tissues is unclear. We developed an in vivo optical sensor of mechanical tension across E-cadherin molecules and a method for statistical classification of migration phenotypes called morphodynamic profiling. We used these approaches in conjunction with cell type specific RNAi and photo-activatable Rac to investigate the in vivo function of E-cadherin during border cell migration. We discovered that E-cadherin plays distinct roles in different subcellular locations. Surprisingly, adhesion between border cells and their substrate, the nurse cells, was required in a positive feedback loop with Rac to stabilize forward directed protrusion and directionally persistent movement. Adhesion between individual border cells was essential for communication of direction and collective guidance. E-cadherin-mediated adhesion between the motile border cells and the polar cells, a pair of non-migratory cells, holds the cluster together and provides each individual cell with polarity. Together, these results establish E-cadherin as a multi-functional core component of the cell migration machinery in vivo.
Another crucial feature of tissue homeostasis is maintaining the proper balance of cell survival and death. In order to eliminate abnormal or danger- ous cells, organisms have evolved cell suicide mechanisms, most famously the form of programmed cell death known as apoptosis. However excess cell death can cause degenerative diseases, so it is crucial to achieve the proper balance between survival and death. We have discovered that cells that have progressed far along the apoptotic pathway, past previously identified points of no return, can actively reverse the process and survive. This process, which we have named anastasis (Greek for “rising to life”) has implications for cancer, degenerative disease, and regenerative medicine.