[R01] Identification of Limiting Mitochondrial Metabolites for the Initiation and Progression of Liver Cancers

Ente: National Cancer Institute

Scadenza: 2031-06-30

Importo max: 559.596 EUR

Paese: US

Descrizione

Project Summary Cancer cells undergo extensive metabolic rewiring to sustain uncontrolled proliferation and adapt to hostile tumor microenvironments. This metabolic reprogramming is often driven by oncogenes and tumor suppressors that remodel cellular bioenergetics, biosynthesis, and redox homeostasis. Primary liver cancer (PLC), such as hepatocellular carcinoma (HCC), exemplifies this complexity. Globally, PLC is among the leading causes of cancer-related death and continues to rise in incidence. Although mitochondria and membranes are central to cancer metabolism, serving as hubs for energy production, lipid biosynthesis, and signaling, the mechanisms by which specific oncogenic alterations reshape organelle metabolism remain poorly understood. In this proposal, we hypothesize that cancer mutations impose distinct alterations in mitochondrial and membrane metabolism that can be leveraged for therapeutic intervention. To address this, my lab developed a rapid organelle immunopurification (mito-IP) technique for profiling metabolites directly from healthy and tumor- bearing livers. Coupled with LC–MS, this approach enables simultaneous detection of mitochondrial metabolites and proteins in cancer cells with defined oncogenic drivers. Using this technology, we uncovered striking metabolic heterogeneity among genetically engineered liver cancers. In particular, Myc;Pten-deficient PLCs exhibit marked accumulation of phosphoethanolamine and phosphatidylethanolamine (PE) species, suggesting enhanced Kennedy-pathway activity. Genetic disruption of the rate-limiting PE synthesis enzyme Pcyt2 selectively impaired the growth of PTEN-null tumors while sparing other genotypes, revealing membrane PE synthesis as a tumor-intrinsic vulnerability. Building upon our preliminary work, this proposal will test the hypothesis that PE synthesis is required for tumor growth and immune evasion in PTEN-deficient primary liver cancers. Specifically, we will: (1) define the requirement for PE synthesis in the initiation, progression, and immune evasion of PTEN-null PLCs using genetic, pharmacologic, and immunologic perturbations; and (2) elucidate the molecular mechanisms linking PI3K signaling, PE accumulation, and TNF receptor (TNFR) regulation using in vivo models, lipid tracing, and cell- surface proteomics. By integrating innovative organelle-targeted metabolomics and genetic mouse models, this work will reveal how lipid metabolism shapes tumor–immune interactions in Pten null PLCs. Istituzione: ROCKEFELLER UNIVERSITY PI: Kivanc Birsoy Progetto: 1R01CA308066-01A1

Settori: National Cancer Institute

Vai al bando originale

Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.