Periodic Reporting for period 1 - PROMIGREX (Mechanical regulation of cell migration by Piezo1 and its implications in epithelial cell turnover)
Okres sprawozdawczy: 2021-04-01 do 2023-03-31
Epithelial cells turn over by cell death and division at some of the fastest rates in the body but must maintain constant numbers while doing so. The rates of cell division must match the rates of cell death or cells could amass into tumours or disappear completely, destroying the barrier they provide to all the organs they encase. This coupling has far-reaching consequences for health and disease, because barrier defects due to cell loss are a hallmark of prevalent diseases like asthma or inflammatory bowel disease, and cell accumulation drives cancer growth. Therefore, identifying the mechanisms controlling epithelial cell turnover may offer new therapeutical opportunities.
Mechanical forces link cell death and division; where crowding activates cells to extrude from the epithelial layer and die and stretch triggers rapid cells to rapidly enter mitosis. Critically, both mechano-responses require the stretch- activated cationic channel Piezo1. The overarching goal of PROMIGREX was to identify the mechanisms by which this channel controls cell division, migration, and death in response to mechanical signals. Specifically, this project aimed at describing how Piezo1 detects cell-cell collisions and redirects migration, how it detects forces and triggers severing of the thin connection between dividing cells, and how its mutations in cancer affect these processes.
Mechanical forces link cell death and division; where crowding activates cells to extrude from the epithelial layer and die and stretch triggers rapid cells to rapidly enter mitosis. Critically, both mechano-responses require the stretch- activated cationic channel Piezo1. The overarching goal of PROMIGREX was to identify the mechanisms by which this channel controls cell division, migration, and death in response to mechanical signals. Specifically, this project aimed at describing how Piezo1 detects cell-cell collisions and redirects migration, how it detects forces and triggers severing of the thin connection between dividing cells, and how its mutations in cancer affect these processes.
Combining quantitative microscopy with pharmacological and genetic manipulations, PROMIGREX has identified Piezo1 as the mechanosensor in charge of mechanical activation of Epidermal Growth Factor Receptor (EGFR), a key protein in development, homeostasis, and cancer, and the ion channels and transporters required for a transient cell volume loss that drives epithelial cell extrusion, required for homeostatic epithelial cell turnover. In addition, PROMIGREX has identified a key role for Piezo1 as a regulator of clathrin-based adhesive structures currently under study for publication later this year. Overall, PROMIGREX deepens our understanding of ion channels as controllers of the most essential cell functions and highlights the importance of basic research as a knowledge-generating discipline.
Despite COVID19-related restrictions, PROMIGREX results were disseminated at international renowned conferences including the Joint BSCB-BSDB meeting (April 2022), EMBO Symposia (May 2022, 2023, September 2023), meeting of the Australian Society for Mechanobiology (November 2022), Biophysical Society Meeting (February 2023), and the Biochemical Society-BSCB meeting (April 2023). Remarkably, in all these conferences, PROMIGREX work was presented after direct invitation by the organisers or selected among submissions to be presented as a talk. In all instances, EU funding was acknowledged.
PROMIGREX has found that Piezo1-dependent EGFR signalling does not involve canonical tyrosine phosphorylation or the kinase activity of EGFR. Instead, this newly identified axis signals via kinases of the Src and p38 families. These findings may help explaining cancer resistance to Tyrosine Kinase Inhibitors and EGFR-blocking antibodies (an unmet medical need) and could be exploited in new therapeutical approaches. Further pre-clinical research will elucidate this.
Despite COVID19-related restrictions, PROMIGREX results were disseminated at international renowned conferences including the Joint BSCB-BSDB meeting (April 2022), EMBO Symposia (May 2022, 2023, September 2023), meeting of the Australian Society for Mechanobiology (November 2022), Biophysical Society Meeting (February 2023), and the Biochemical Society-BSCB meeting (April 2023). Remarkably, in all these conferences, PROMIGREX work was presented after direct invitation by the organisers or selected among submissions to be presented as a talk. In all instances, EU funding was acknowledged.
PROMIGREX has found that Piezo1-dependent EGFR signalling does not involve canonical tyrosine phosphorylation or the kinase activity of EGFR. Instead, this newly identified axis signals via kinases of the Src and p38 families. These findings may help explaining cancer resistance to Tyrosine Kinase Inhibitors and EGFR-blocking antibodies (an unmet medical need) and could be exploited in new therapeutical approaches. Further pre-clinical research will elucidate this.
EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. While EGF ligand and mechanical inputs can activate EGFR-ERK signaling, the molecules linking mechanical force to this axis have remained mysterious. PROMIGREX found that Piezo1 provides the missing link between mechanical signals and EGFR-ERK activation. These findings suggest that mechanical activation via Piezo1, Src, and p38 may be more relevant to controlling repair, regeneration, and cancer growth than tyrosine kinase signaling via canonical EGF signaling. These findings connect cancer biology, mechanobiology, and drug discovery and indentify an attractive therapeutic approach.