| Date |
Friday, April 7, 2017 (16:00 – onward) |
| Room |
7th Floor, Seminar Room 1, IDAC Center for Basic Aging Research |
| Title |
Cell competition with normal epithelial cells promotes apical elimination of transformed cells through Warburg effect-like metabolic changes |
| Speaker |
Shunsuke Kon |
| Affiliation |
Institute for Genetic Medicine, Hokkaido University Division of Molecular Oncology |
| Organizer |
Yasuhisa Matsui (Cell Resoruse Center for Biomedica Research・ext 8571) |
| Abstract |
Recent studies have revealed that newly emerging transformed cells are often apically extruded from epithelial tissues. Normal epithelial cells are able to recognize and actively eliminate transformed cells, a process called Epithelial Defence Against Cancer (EDAC). However, the molecular mechanisms underlying this anti-tumourigenic phenomenon remain poorly understood. In this seminar, I would like to discuss that the presence of the surrounding normal cells profoundly diminishes mitochondrial membrane potential in RasV12-transformed cells in a non-cell-autonomous fashion. In addition, glucose uptake and expression level of lactate dehydrogenase A (LDHA) are elevated in RasV12 cells mixed with normal cells, giving rise to higher lactate production. The mitochondrial dysfunction is driven by upregulation of pyruvate dehydrogenase kinase 4 (PDK4), and knockdown/knockout of PDK4 or treatment with PDK inhibitor dichloroacetate (DCA) substantially suppresses the elimination of RasV12-transformed cells. Furthermore, EDAC from the surrounding normal cells, which involves Filamin, drives the Warburg effect-like metabolic alteration via regulating EPLIN in RasV12 cells. Moreover, using the novel cell competition mouse model, I will show that the PDK-mediated metabolic changes play an active role in the elimination of RasV12-transformed cells ex vivo and in vivo. Collectively, the non-cell-autonomous metabolic modulation is a crucial regulator for the competitive interaction between normal and transformed epithelial cells in mammals, shedding light on the unexplored events occurring at the initial stage of carcinogenesis. |
