Spencer Freeman
Hospital for Sick Children, University of Toronto, Ontario, Canada
Under pressure: mechanotransduction from lysosomes and consequences on tissue homeostasis
Spencer Freeman received his Ph.D. from the University of British Columbia. Since then, he has investigated basic immunobiology, first as a post-doctoral fellow at the Hospital for Sick Children, then as faculty in the SickKids Research Institute and the University of Toronto where he holds a Tier II CIHR Research Chair in Immune Surveillance. He has made key contributions to understanding specialized types of endocytosis in myeloid cells including phagocytosis and macropinocytosis using imaging-based approaches that range from single molecule tracking to intravital microscopy. Recently, his laboratory has explored the mechanisms by which immune cells control organelle volume and sense mechanical perturbations on these organelles. As such, his team is working to understand the movement of ions and solutes across the limiting membrane of endosomes, lysosomes, and phagosomes in macrophages using multidisciplinary approaches. A second line of research relates to the cytoskeleton in immune cells, how it supports mechanisms of their surveillance, and how dysregulation of genes that control the cytoskeleton lead to immune related diseases.
In this seminar, Dr Freeman will discuss mechanisms that build ion gradients in lysosomes that ultimately support cell metabolism. He will then describe the collapse of these gradients in pathological states via a mechanosensitive cation channel, TMEM63A. Using diverse models for lysosomal stress, he will describe how this mechanism influences the responses of tissue macrophages.
Selected publications
- Pressure sensing of lysosomes enables control of TFEB responses in macrophages. Cai R, Scott O, Ye G, Le T, Saran E, Kwon W, Inpanathan S, Sayed BA, Botelho RJ, Saric A, Uderhardt S, Freeman SA. Nat Cell Biol. 2024 26(8):1247-1260
- Redistribution of the glycocalyx exposes phagocytic determinants on apoptotic cells. Le T, Ferling I, Qiu L, Nabaile C, Assunção L, Roskelley CD, Grinstein S, Freeman SA. Dev Cell. 2024 59(7):853-868.e7
- Two-pore channels regulate endomembrane tension to enable remodeling and resolution of phagolysosomes. Chadwick SR, Barreda D, Wu JZ, Ye G, Yusuf B, Ren D, Freeman SA. Proc Natl Acad Sci USA. 2024 121(8):e2309465121
- ClC-7 drives intraphagosomal chloride accumulation to support hydrolase activity and phagosome resolution. Wu JZ, Zeziulia M, Kwon W, Jentsch TJ, Grinstein S, Freeman SA. J Cell Biol. 2023 222(6):e202208155
- Lipid peroxidation increases membrane tension, Piezo1 gating, and cation permeability to execute ferroptosis. Hirata Y, Cai R, Volchuk A, Steinberg BE, Saito Y, Matsuzawa A, Grinstein S, Freeman SA. Curr Biol. 2023 33(7):1282-1294.e5