Integrated multi-omics analysis of RB-loss identifies widespread cellular programming and synthetic weaknesses
Swetha Rajasekaran1,2, Jalal Siddiqui1,2, Jessica Rakijas1,2
1Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
Abstract:
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.
Insights
RB protein loss triggers cellular reprogramming, altering cell metabolism and stress responses. This study identifies key metabolic pathways crucial for the growth of RB-depleted cancer cells, offering potential therapeutic targets.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Research
Background:
- Retinoblastoma (RB) protein inactivation is a key event in cancer development.
- The precise molecular consequences of RB loss in human cells remain incompletely understood.
Purpose of the Study:
- To comprehensively analyze the cellular reprogramming induced by RB depletion in non-tumorigenic human cells.
- To identify molecular pathways and metabolic changes essential for the proliferation of RB-deficient cancer cells.
Main Methods:
- Quantitative measurement of transcriptional, proteomic, and metabolic profiles following RB depletion in RPE1 cells.
- Comparison of cellular alterations with data from Retinoblastoma and Small Cell Lung Cancer patient tumors.
- In vivo validation using RB1-/- cells and Drosophila E2f1-RNAi models to assess the impact of pathway inhibition on cell growth.
Main Results:
- RB depletion causes widespread transcriptional, proteomic, and metabolic reprogramming, including changes in E2F-regulated factors and cell stress responses.
- Identified non-E2F-regulated pathways that are sensitive to RB loss, potentially supporting RB-depleted cell growth.
- Observed conservation of these molecular alterations in human RB1-/- tumors, validating the RPE1 cell model.
Conclusions:
- RB loss induces significant cellular reprogramming with conserved alterations in human cancers.
- Key metabolic pathways are essential for the survival and growth of RB-deleted human cells.
- These findings highlight critical metabolic vulnerabilities in RB-deficient cancers that could be therapeutically exploited.
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