Characterization of proteome-size scaling by integrative omics reveals mechanisms of proliferation control in cancer

ABSTRACT: Many cell types exhibit remarkable size homogeneity through successive divisions. In both yeast and humans, size homogeneity during division cycles is a result of tight control on the concentration of cell-cycle inhibitors such as WHI5 or RB1 (Retinoblastoma 1) proteins respectively. However, size control is often lost during oncogenesis, correlating with aggression. How size control is affected by mutations which drive proliferation, such as those of the RAS-ERK pathway, or even loss of RB1 itself, is poorly understood. Using quantitative single cell imaging of different melanoma cell lines, we show that melanoma cells exhibit both inter- and intra-line size variability. Integration of imaging with multi-omic data demonstrates that the translation machinery, G2 regulators, inflammatory mediators and growth-regulatory proteins are key determinants of size in melanoma. Theoretical modelling suggests that the cell size of daughter cells is determined by biosynthetic processes and engagement of stress responses in the mother. Biosynthesis and stress in mother cells impacts the synthesis of heritable prodivision factors like Cyclin D1 (CCND1) which control cell progression by inhibiting RB1 in concentration dependent fashions Small cell sizes and uniform populations are driven by robust DNA repair and increased levels of biosynthetic factors which promote CCDN1 accumulation. We propose that increased size and size-heterogeneity in BRAF and NRAS mutated cells is determined by stress or DNA damage in mother’s division cycle that slows cycle progression in the daughters. Such events lead to increased size and senescent-like states. Taken together our data suggest that oncogenic events, such as the dysregulation of MAPK signalling, provide a means to circumvent normal mechanisms of size regulation and increase cell-to-cell variations in size which may drive disease.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: James Wright  

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD028339 | Pride | 2023-01-03

REPOSITORIES: Pride