Activation of oncogenes in normal cells causes cell proliferation arrest, termed oncogene-induced senescence (OIS), which acts as a protective brake against tumor formation. Release or bypass of this senescence brake by genomic alterations promotes oncogene-driven cancer. Despite cell cycle arrest, senescent cells display a distinct metabolic phenotype with hyperactive TCA cycle, mitochondrial respiration, and fatty acid oxidation to maximize energy production. We hypothesise that the metabolic rewiring acts as a key effector of OIS and overcoming these shifts in metabolism may cause senescence escape and lead to tumorigenesis. We therefore aim to characterize the metabolic profile of OIS cells to underpin the substantial alterations and to investigate the role of Cystathionine Beta Synthase (CBS), a candidate gene identified from a genome-wide RNAi screen in AKT-induced senescence cells, in OIS and tumorigenesis.
We have performed a series of ‘omics’ studies to gain an in-depth understanding of OIS and escape thereof. Our findings indicate the overall metabolome similarity between AKT and HRAS hyperactivation induced senescence regardless of their distinct senescence induction mechanism. Our studies help solve another puzzle in cellular senescence.
CBS expression has been previously reported to be downregulated in hepatocellular carcinoma and associated with poor prognosis. Here, we have validated CBS loss in OIS leads to senescence escape which again highlights a potential tumour suppressive role in cancer. Importantly, enhanced CBS expression and function in gastric cancers and hepatocellular carcinomas induce senescence. The cancer cell growth has been dramatically slowed down. The metabolic alterations including enhanced H2S production from CBS, and elimination of excess intracellular homocysteine are believed to be responsible for cancer cell senescence induction. Our approach is to perform genome-wide transcriptome study and global metabolomic study to further establish the substantial functional role of CBS in OIS and cancer. The goal of this project is to harnessing senescence in cancers through CBS and target senescent cancer cells through senolytic compounds or immunotherapy.
In conclusion, the in-depth characterization of metabolic reprogramming in OIS will uncover the cellular vulnerabilities that can be exploited therapeutically.