Project Details
Projekt
Targeting lipid synthesis and NADPH regeneration in cancer
Applicants
Daniel Dauch, Ph.D.; Professorin Dr. Almut Schulze
Subject Area
Hematology, Oncology
Term
from 2015 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 267467939
Hepatic lipogenesis is an essential cellular process that allows for the de novo synthesis of fatty acids for energy storage, membrane biosynthesis and production of signaling molecules. We could now show that an enhanced lipogenesis triggered by an activation of the Liver X receptor alpha (LXRα) represents a potential new therapeutic strategy against liver cancer (HCC). Treatment studies in liver cancer mouse models and in human and murine HCC cells revealed that pharmacological stimulation of LXRα in combination with a simultaneous blockade of the Raf kinase results in lipid accumulation and death of liver cancer cells and prolongs survival of tumor bearing mice. We observed that LXRα activation was in general well tolerated by mice, indicating that a therapeutic window enables the feasibility of such a therapeutic approach. Interestingly, we identified the Raf inhibitor and liver cancer drug Sorafenib as a moderate LXRα activator, and could show that enhanced LXRα signaling contributes to its efficacy. However, full activation of LXRα by treatment with established pharmacological LXRα agonists strongly improved the therapeutic outcome of Sorafenib in HCC.We also obtained evidence that inhibition of lipid synthesis can be an effective strategy for cancer treatment. We could show that HCC cells harboring different oncogenic drivers (Nras, Akt) exhibit specific metabolic phenotypes, with Akt-driven liver cancer cells selectively depending on acetate for the synthesis of acetyl-CoA. Inhibition of Acetyl-CoA synthetase 2 (Acss2), the enzyme catalyzing this reaction, altered acetate metabolism and histone acetylation, and reduced cell viability in Akt-driven HCCs. Moreover, we have performed functional genetic screens to identify additional metabolic vulnerabilities in liver cancer that may represent novel therapeutic targets.Within this proposal, we want to apply detailed genetic and metabolic analyses in vitro and in vivo to investigate how liver cancer cells are affected by pharmacological and genetic manipulation of lipogenic pathways. We want to characterize the cellular stress response induced by LXRα induction in liver cancer and elucidate the molecular mechanisms defining the observed therapeutic window. Furthermore, we want to evaluate the role of Raf in LXRα mediated cellular stress induction and identify those components of the Raf signaling pathway that are implicated in the synergistic response to LXRα activation in HCC. We will also determine the essential role of Acss2 in liver cancer and identify the cellular processes controlled by Acss2-dependent regulation of acetate metabolism. For this we will investigate the consequences of Acss2 inhibition on lipid synthesis and epigenetic regulation via histone acetylation. In addition, we will characterize the newly identified metabolic vulnerabilities in different HCC genotypes to evaluate their potential as therapeutic targets in liver cancer.
DFG Programme
Research Units
