Our lab studies how epithelia maintain a functional barrier and proper cell numbers, despite turning over at high rates by cell death and cell division. We found mechanics control both opposing processes: when cells are too sparse, stretch activates cell division and when too many, crowding activates cell death by ‘epithelial cell extrusion’. While we first discovered extrusion as a process that eliminates dying cells without creating any gaps within the epithelium, we later discovered that most epithelial cells die as a result of live cell extrusion. Due to the significant role extrusion plays in epithelial cell death, a variety of diseases, ranging from bacterial and viral pathogenesis, asthma, and cancer, can result when it is misregulated. Inflammation and infection can result from excess extrusion whereas aberrant basal cell extrusion (back into the tissue epithelia encase) can drive cell invasion and de-differentiation in a class of aggressive tumours. We are currently using organoids and mouse lung slices to investigate the fate of cells that invade by basal extrusion and the signalling that drives this.
PhD students:
- Saranne Mitchell
- Faith Fore
- Lily Gates
People
HFSP and MSCA Research Fellow
Professor of Cell Biology
Research Associate
Projects
Mechanisms controlling extrusion
Apoptotic stimuli through caspases and mechanosensing of a crowded state through Piezo determine whether a cell is going to extrude or not. A cell fated to extrude signals to its neighbors, via a lipid called sphingosine-1-phosphate (S1P). S1P binds its cognate receptor S1P2 on surrounding cells, inducing the formation of an actomyosin cable basolaterally to squeeze the extruding cell up and out of the epithelium. What might happen if extrusion is dysregulated? Too much extrusion or defects in the extrusion pathway may lead to inflammatory disease. On the other hand, cancer cells may lose the ability to apically extrude and be forced to go basally, leading to invasion.
Extrusion misregulation in asthma
Asthma is characterized by airway constriction, excess mucus, and inflammation. We use mouse ex vivolung slices to show that the inflammation and mucus secretion results from the excessive crowding due to mechanical bronchoconstriction, which causes so much cell extrusion that it destroys the airway epithelial barrier. Surprisingly, reversing bronchoconstriction with albuterol ((ALB), the current therapy) did not block this destruction but actually made it worse. However, inhibiting stretch-activated channels (GD) prevented extrusion, inflammation, and mucus secretion. Our findings propose a new etiology for asthma where the mechanical crowding from bronchoconstriction causes so much extrusion that it compromises the barrier, triggering subsequent inflammation.
Extrusion misregulation and cancer cell invason
One effect of unchecked cell extrusion is cancer invasion and metastasis. Using the transparent zebrafish embryonal skin as a model, we found that cells expressing an oncogenic KRas mutation—driver of pancreatic, colon, and lung cancers—are likely to extrude. However, instead of extruding apically out of the body, they are redirected. We call this process basal cell extrusion (BCE): cancer cells aberrantly extrude basally, back into the tissue that the epithelium encases. Surprisingly, the cancer cell sheds its apical membrane, along with surface epithelial traits, simultaneous with BCE, demonstrating a novel mechanical loss of epithelial identity. This endows invading KRas cells with new plasticity and allows differentiation into other cell types, reminiscent of stromal and neuronal cell populations in human pancreatic cancer.
Publications
Awards
Cancer Research UK Programme Grant: The role of basal extrusion in cancer metastasis
Wellcome Trust Investigator Award: The role of epithelial cell extrusion in asthma
Biotechnology and Biological Sciences Research Council sLoLa grant: Regulation of epithelial and endothelial cell-cell junctions by mechanical forces (co-investigator)
Academy of Medical Sciences Professorship
American Asthma Foundation: Inhibiting bronchoconstriction-dependent airway epithelial extrusion to block the asthma inflammatory cycle
People
HFSP and MSCA Research Fellow
Professor of Cell Biology
Research Associate
Projects
Mechanisms controlling extrusion
Apoptotic stimuli through caspases and mechanosensing of a crowded state through Piezo determine whether a cell is going to extrude or not. A cell fated to extrude signals to its neighbors, via a lipid called sphingosine-1-phosphate (S1P). S1P binds its cognate receptor S1P2 on surrounding cells, inducing the formation of an actomyosin cable basolaterally to squeeze the extruding cell up and out of the epithelium. What might happen if extrusion is dysregulated? Too much extrusion or defects in the extrusion pathway may lead to inflammatory disease. On the other hand, cancer cells may lose the ability to apically extrude and be forced to go basally, leading to invasion.
Extrusion misregulation in asthma
Asthma is characterized by airway constriction, excess mucus, and inflammation. We use mouse ex vivolung slices to show that the inflammation and mucus secretion results from the excessive crowding due to mechanical bronchoconstriction, which causes so much cell extrusion that it destroys the airway epithelial barrier. Surprisingly, reversing bronchoconstriction with albuterol ((ALB), the current therapy) did not block this destruction but actually made it worse. However, inhibiting stretch-activated channels (GD) prevented extrusion, inflammation, and mucus secretion. Our findings propose a new etiology for asthma where the mechanical crowding from bronchoconstriction causes so much extrusion that it compromises the barrier, triggering subsequent inflammation.
Extrusion misregulation and cancer cell invason
One effect of unchecked cell extrusion is cancer invasion and metastasis. Using the transparent zebrafish embryonal skin as a model, we found that cells expressing an oncogenic KRas mutation—driver of pancreatic, colon, and lung cancers—are likely to extrude. However, instead of extruding apically out of the body, they are redirected. We call this process basal cell extrusion (BCE): cancer cells aberrantly extrude basally, back into the tissue that the epithelium encases. Surprisingly, the cancer cell sheds its apical membrane, along with surface epithelial traits, simultaneous with BCE, demonstrating a novel mechanical loss of epithelial identity. This endows invading KRas cells with new plasticity and allows differentiation into other cell types, reminiscent of stromal and neuronal cell populations in human pancreatic cancer.
Publications
Awards
Cancer Research UK Programme Grant: The role of basal extrusion in cancer metastasis
Wellcome Trust Investigator Award: The role of epithelial cell extrusion in asthma
Biotechnology and Biological Sciences Research Council sLoLa grant: Regulation of epithelial and endothelial cell-cell junctions by mechanical forces (co-investigator)
Academy of Medical Sciences Professorship
American Asthma Foundation: Inhibiting bronchoconstriction-dependent airway epithelial extrusion to block the asthma inflammatory cycle
Our Partners
The Academy of Medical Sciences
Biotechnology and Biological Sciences Research Council
Group lead
Professor of Cell Biology