טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentFarber Hodaya
SubjectIdentifing Metabolic Alterations and Vulnerabilites in
Senescent Cancer Cells
DepartmentDepartment of Biology
Supervisor Professor Tomer Shlomi


Abstract

Cellular senescence, cell cycle arrest due to stress conditions, is a defense mechanism against accumulation of mutations and tumorigenesis. Therapy-induced senescence (TIS) is caused by treating cancer cells with sub-cytotoxic doses of chemotherapy. Senescence was thought of as irreversible, hence, serving as a valid end-point for cancer therapy, inhibiting cancer progression. New evidence reveals ways for escaping senescence, resulting in senescent cancer cells which are resistant to classical chemotherapy, which can in time lead to cancer relapse. Moreover, the senescence process is accompanied by senescence-associated secretory phenotype (SASP), involving the secretion of inflammatory cytokines that enhances inflammation in the tumor microenvironment and cancer progression. Our research aims to identify cellular metabolic alterations and vulnerabilities associated with TIS. To address this challenge, we used LC-MS based metabolomics and isotope tracing to characterize metabolic alterations in cancer cell lines treated with the chemotherapeutic drug doxorubicin to induce TIS. Isotope tracing experiments with 13C glucose and glutamine revealed decreased pyruvate dehydrogenase (PDH) activity in senescent cells (versus non-proliferating quiescent cells) and an overall decrease in mitochondrial respiration. We further observe an increase in the relative contribution of glucose versus glutamine-derived TCA cycle anaplerosis via pyruvate carboxylase in TIS. Additionally, our metabolomics results show major changes in the intracellular concentration of phosphoethanolamine and CDP-ethanolamine in TIS, suggesting altered lipid metabolism. Our results call for further research on characterizing metabolic alterations associated with TIS and finding of induced essentiality of metabolic enzymes that could be targeted for therapeutic purposes.