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

Swetha Rajasekaran, Jalal Siddiqui, Jessica Rakijas, Brandon Nicolay, Chenyu Lin, Eshan Khan, Rahi Patel, Robert Morris, Emanuel Wyler, Myriam Boukhali, Jayashree Balasubramanyam, R. Ranjith Kumar, Capucine Van Rechem, Christine Vogel, Sailaja V. Elchuri, Markus Landthaler, Benedikt Obermayer, Wilhelm Haas, Nicholas Dyson, Wayne Miles

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number977
JournalCommunications Biology
Volume4
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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