The goal of our work is to discover fundamental mechanisms that control cell growth and size in all eukaryotic cells. Our recent work has focused on two key questions: 1. How do cells measure and limit growth to control cell size? In all cells, key cell cycle transitions occur only when sufficient growth has occurred, which ensures that proliferating cells maintain a specific size. Thus, cells must convert growth to a proportional signal that triggers cell cycle progression when it reaches a threshold. The mechanisms by which cells measure growth and trigger cell cycle transitions have remained deeply mysterious. Our recent work suggests that vesicles that drive plasma membrane growth deliver phosphatidylserine to the growing membrane, which recruits conserved signaling proteins to generate a signal that is proportional to the extent of growth. Furthermore, we discovered a signaling pathway that could read the growth-dependent signal and trigger cell cycle progression when it reaches a threshold. Growth-dependent signaling suggests a simple and broadly applicable solution to control of cell growth and size. 2. What are the signals that control cell growth and size? Observations reaching back over 60 years point to close relationships between control of cell growth and size. Thus, growth rate is proportional to nutrient availability, cell size is proportional to growth rate, and growth rate is proportional to cell size. These relationships appear to hold across all orders of life, which suggest that they reflect fundamental principles, yet the underlying mechanisms have remained elusive. We discovered that signals arising from a conserved TORC2 signaling network enforce proportional relationships between nutrient availability, cell growth, and cell size. For example, our work suggests that TORC2-dependent signals that set growth rate also set the threshold amount of growth required for cell cycle progression, which would provide a simple mechanistic explanation for the proportional relationship between cell size and growth rate. Together, these new discoveries support transformational hypotheses that could broadly explain how cell growth and size are controlled. In our future work, we will test the key hypotheses arising from our discoveries, while also carrying out mechanistic analysis to further map the remarkable signaling networks that control cell growth and size. We will also begin translating our discoveries in yeast into an understanding of how cell growth and size are controlled in vertebrate cells.
Severe defects in cell growth and size are a nearly universal feature of cancer cells and have provided the basis for cancer pathology for over 80 years, yet the underlying causes are unknown. The long-term goal of our work is to discover how control of cell growth and size works in normal cells, and how it goes wrong in cancer. With this knowledge, we hope to identify novel vulnerabilities of cancer cells that can be exploited to improve therapies.
