Integrated multi-omics analysis of RB-loss identifies widespread cellular programming and synthetic weaknesses

Swetha Rajasekaran et al. integrate transcriptional, proteomic, and metabolomic data to explore how cells adapt to inactivation of RB1, a hallmark of cancer. Combined with their genetic analyses in a Drosophila model, the authors identify key metabolic pathways that may be involved in the growth of RB1-depleted cancer cells. Inactivation of RB is one of the hallmarks of cancer, however gaps remain in our understanding of how RB-loss changes human cells. Here we show that pRB-depletion results in cellular reprogramming, we quantitatively measured how RB-depletion altered the transcriptional, proteomic and metabolic output of non-tumorigenic RPE1 human cells. These profiles identified widespread changes in metabolic and cell stress response factors previously linked to E2F function. In addition, we find a number of additional pathways that are sensitive to RB-depletion that are not E2F-regulated that may represent compensatory mechanisms to support the growth of RB-depleted cells. To determine whether these molecular changes are also present in RB1(-/-) tumors, we compared these results to Retinoblastoma and Small Cell Lung Cancer data, and identified widespread conservation of alterations found in RPE1 cells. To define which of these changes contribute to the growth of cells with de-regulated E2F activity, we assayed how inhibiting or depleting these proteins affected the growth of RB1(-/-) cells and of Drosophila E2f1-RNAi models in vivo. From this analysis, we identify key metabolic pathways that are essential for the growth of pRB-deleted human cells.

Automated summary

Swetha Rajasekaran and colleagues integrated multiple types of data to investigate how cells adapt to RB1 inactivation, a hallmark of cancer. They identified key metabolic pathways that may be involved in the growth of RB1-depleted cancer cells and found that RB-depletion resulted in cellular reprogramming. The study also revealed widespread changes in metabolic and cell stress response factors, some of which were not E2F-regulated, suggesting compensatory mechanisms to support the growth of RB-depleted cells.