MicroRNA-mediated modulation of metabolic pathways as a therapeutic principle in hepatocellular carcinoma.

• Applicant: Asha Balakrishnan, Ph.D.
• Subject Area: Gastroenterology ; Hematology, Oncology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457476621

Hepatocellular carcinoma (HCC), the most common type of liver cancer, has multiple etiologies, widespread prevalence, and is a significant global economic burden. Being largely refractory to current treatments, HCC is the fourth leading cause of cancer related deaths, world-wide, with a median survival of only six to eight months. Therefore, novel and more effective treatments need to be developed. The propensity of hepatocytes to readily take-up nucleic acids provides an avenue for the development of small nucleic acid-based drugs, as effective therapeutics against HCC. Small non-coding microRNAs (miRNAs) are such a class of nucleic acids that are important regulators in HCCs and emerge as promising therapeutic targets. MiRNAs affect a wide range of functions, including metabolism. Metabolic reprogramming is a central hallmark of cancer, including HCCs. Metabolic alterations can characterize HCC tumors both, at the molecular and phenotypic levels. Although deregulation of oncogenes and tumor suppressors results in altered metabolic signatures in cancer, metabolites themselves can be oncogenic or tumor suppressive. Thus, therapeutic regulation of specific metabolites via miRNA modulation holds promise in HCC treatment. Despite the enormous therapeutic potential of miRNA modulation, their functional relevance in cancer metabolism is only just emerging. Also, whether miRNAs may differentially regulate metabolism during tumor regression and the corresponding underlying mechanisms need elucidation. I propose in-depth functional analyses on selected oncogenic miRNAs identified from miRNA profiling of samples from conditional doxycycline-regulated c-MYC-driven liver tumor mice, at four stages of tumor development and regression. Specifically, these miRNAs are differentially deregulated between established and regressing tumors. I will especially focus on these selected miRNAs, also, since they have predicted targets in energy, central carbohydrate, amino acid, and lipid metabolism, metabolic pathways often reprogrammed in HCC. Targeted metabolomics will map their metabolic flux as tumors progress and regress. I already have corresponding global mRNA expression data for these samples, which will enable me to discover novel, significantly deregulated miRNA-mRNA circuitries within metabolic pathways of interest. As a proof of principle, the effect of the most potent of these oncogenic miRNAs on the metabolome will be determined. I will employ in silico, in vitro, and in vivo functional analyses to study the molecular mechanisms, by which selected miRNAs alone, or in combination with the proven potent tumor suppressor, miR-342-3p, may affect liver tumor metabolism during tumor progression. Also, we will determine whether their therapeutic intervention would lead to attenuation of tumor development or induction of regression. This is a crucial step for the development of novel and more effective therapeutic options for this currently intractable disease.

• DFG Programme: Research Grants